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Background: Chronic obstructive pulmonary disease (COPD) is a significant respiratory disorder in humans characterized by persistent airway constriction or obstruction due to chronic bronchitis and pulmonary emphysema. Various methods of inducing COPD in mouse models are frequently used in COPD research; however, these cannot completely reproduce histopathologic lesions. This study aimed to establish a new COPD mouse model that reproduces histopathological lesions closely resembling clinical COPD within a shorter induction time., Methods: The new strategy involved the co-administration of porcine pancreatic elastase (PPE) and lipopolysaccharide (LPS), with PPE intended to induce pulmonary emphysema and LPS intended to induce chronic bronchitis. Male C57BL/6J mice were administered PPE (8 U/kg) on days 0 and 3 and LPS (400 µg/kg) on days 6, 9, 12, and 15. Each administration was performed using a noninvasive intubation-mediated intratracheal instillation method with a laryngoscope., Results: Postmortem examination on day 22 revealed that pulmonary emphysema and chronic bronchitis were simultaneously induced in 90.91% of the lung lobes. Molecular studies revealed higher messenger ribonucleic acid (mRNA) expression levels of interleukin-6(IL-6) and matrix metalloproteinase-12(MMP-12) associated with the pathogenesis of COPD., Conclusion: A new method was developed to establish a COPD mouse model that displays a more severe representation of the histopathological findings of clinical COPD than previous COPD models. It also reduces the time required for model induction. This newly developed COPD mouse model is expected to be a valuable tool for the pathogenesis and therapeutic research on human COPD., Competing Interests: Declarations Ethics approval and consent to participate This study was conducted following the ARRIVE guidelines. This study obtained approval from the Institutional Animal Care and Use Committee at Konkuk University, Seoul, Republic of Korea, for all experimental animal usage and procedures, with approval number KU23078. All animal experiments were performed under anesthesia to minimize suffering to the mice. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Combined pulmonary fibrosis and emphysema (CPFE) is a distinct syndrome associated with heavy smoking. The fibrotic component of the disease is generally believed to be superimposed on previously existing pulmonary emphysema, but the mechanisms responsible for these changes remain poorly understood. To better understand the pathogenesis of CPFE, we performed a series of experiments that focused on the relationships between lung elastic fibers, cigarette smoke, and secondary lung injury. The results indicate that even brief smoke exposure predisposes the lung to additional forms of lung injury that may cause alveolar wall fibrosis. The proinflammatory activity of smoke-induced structural alterations in elastic fibers may contribute to this process by enhancing secondary lung inflammation, including acute exacerbations of chronic obstructive pulmonary disease. Furthermore, the levels of the unique elastin crosslinks, desmosine and isodesmosine, in blood, urine, and sputum may serve as biomarkers for the transition from pulmonary emphysema to interstitial fibrosis. While the long-term effects of these inflammatory reactions were not examined, the current studies provide insight into the potential relationships between elastic fiber injury, cigarette smoke, and secondary lung injury. Determining the mechanisms involved in combined pulmonary emphysema and fibrosis and developing a sensitive biomarker for this type of lung injury may permit timely therapeutic intervention that could mitigate the high risk of respiratory failure associated with this condition.

Ethnopharmacological Relevance: Medicinal plants have shown promise in the search for new treatments of pulmonary emphysema. Anadenanthera colubrina, a species native to the Caatinga biome in northeastern Brazil, is widely recognized and traditionally employed in the treatment of pulmonary diseases. Many studies corroborate popular knowledge about the medicinal applications of A. colubrina, which has demonstrated a remarkable variety of pharmacological properties, however, its anti-inflammatory and antioxidant properties are highlighted., Aim of the Study: The objective of this study was to investigate the anti-inflammatory potential of the crude hydroethanolic extract of A. colubrina var. cebil (Griseb.) Altschul on pulmonary emphysema in rats as well as to determine its potential genotoxic and cytotoxic effects using the micronucleus assay., Materials and Methods: The stem bark of the plant was collected in Pimenteiras-PI and sample was extracted by maceration using 70% ethanol. A portion of the extract underwent phytochemical analyses using TLC and HPLC. In this study, 8-week-old, male Wistar rats weighing approximately ±200 g was utilized following approval by local ethics committee for animal experimentation (No. 718/2022). Pulmonary emphysema was induced through orotracheal instillation of elastase, and treatment with A. colubrina extract or dexamethasone (positive control) concomitantly during induction. Twenty-eight days after the initiation of the protocol, plasma was used for cytokine measurement. Bronchoalveolar lavage (BAL) was used for leukocyte count. After euthanasia, lung samples were processed for histological analysis and quantification of oxidative stress markers. The micronucleus test was performed by evaluating the number of polychromatic erythrocytes (PCE) with micronuclei (MNPCE) to verify potential genotoxic effects of A. colubrina. A differential count of PCE and normochromatic erythrocytes (NCE) was performed to verify the potential cytotoxicity of the extract. Parametric data were subjected to normality analysis and subsequently to analysis of variance and Tukey or Dunnett post-test, non-parametric data were treated using the Kruskal-Wallis test with Dunn's post-test for unpaired samples. P value < 0.05 were considered significant., Results: The A. colubrina extract did not show a significant increase in the number of MNPCE (p > 0.05), demonstrating low genotoxicity. No changes were observed in the PCE/NCE ratio of treated animals, compared with the vehicle, suggesting low cytotoxic potential of the extract. A significant reduction (p < 0.05) in neutrophilic inflammation was observed in the lungs of rats treated with the extract, evidenced by presence of these cells in both the tissue and BAL. The extract also demonstrated pulmonary antioxidant activity, with a significant decrease (p < 0.05) in myeloperoxidase, malondialdehyde, and nitrite levels. TNFα, IL-1β, and IL-6 levels, as well as alveolar damage, were significantly reduced in animals treated with A. colubrina extract. Phytochemical analyses identified the presence of phenolic compounds and hydrolysable tannins in the A. colubrina extract., Conclusions: The findings of this study highlights the safety of the hydroethanolic extract of Anadenanthera colubrina, and demonstrates its potential as a therapeutic approach in the treatment of emphysema. The observed properties of this medicinal plant provide an optimistic outlook in the development of therapies for the treatment of pulmonary emphysema., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Pulmonary emphysema involves progressive destruction of alveolar walls, leading to enlarged air spaces and impaired gas exchange. While the precise mechanisms responsible for these changes remain unclear, there is growing evidence that the extracellular matrix plays a critical role in the process. An essential feature of pulmonary emphysema is damage to the elastic fiber network surrounding the airspaces, which stores the energy needed to expel air from the lungs. The degradation of these fibers disrupts the mechanical forces involved in respiration, resulting in distension and rupture of alveolar walls. While the initial repair process mainly consists of elastin degradation and resynthesis, continued alveolar wall injury may be associated with increased collagen deposition, resulting in a mixed pattern of emphysema and interstitial fibrosis. Due to the critical role of elastic fiber injury in pulmonary emphysema, preventing damage to this matrix component has emerged as a potential therapeutic strategy. One treatment approach involves the intratracheal administration of hyaluronan, a polysaccharide that prevents elastin breakdown by binding to lung elastic fibers. In clinical trials, inhalation of aerosolized HA decreased elastic fiber injury, as measured by the release of the elastin-specific cross-linking amino acids, desmosine, and isodesmosine. By protecting elastic fibers from enzymatic and oxidative damage, aerosolized HA could alter the natural history of pulmonary emphysema, thereby reducing the risk of respiratory failure.

Elastin is an extracellular matrix protein (ECM) that supports elasticity of the lung, and in patients with chronic obstructive pulmonary disease (COPD) and emphysema, the structural changes that reduce the amount of elastic recoil, lead to loss of pulmonary function. We recently demonstrated that elastin is a target of peptidyl arginine deiminase (PAD) enzyme-induced citrullination, thereby leading to enhanced susceptibility of this ECM protein to proteolysis. This study aimed to investigate the impact of PAD activity in vivo and furthermore assessed whether pharmacological inhibition of PAD activity protects against pulmonary emphysema. Using a Serpina1a-e knockout mouse model, previously shown to develop inflammation-mediated emphysema, we validated the involvement of PADs in airway disease. In line with emphysema development, intratracheal administration of lipopolysaccharide in combination with PADs provoked significant airspace enlargement ( P < 0.001) and diminished lung function, including loss of lung tissue elastance ( P = 0.0217) and increases in lung volumes ( P = 0.0463). Intraperitoneal treatment of mice with the PAD inhibitor, BB-Cl-amidine, prevented PAD/LPS-mediated lung function decline and emphysema and reduced levels of citrullinated airway elastin ( P = 0.0199). These results provide evidence for the impact of PADs on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD. NEW & NOTEWORTHY This study provides evidence for the impact of peptidyl arginine deiminase (PAD) enzymes on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.

Chronic obstructive pulmonary disease (COPD) is a common disease with high global morbidity and mortality. Macrophages release IL-1β and orchestrate airway inflammation in COPD. Previously, we explored the role of a new lncRNA, LincR-PPP2R5C, in regulating Th2 cells in asthma. Here, we established a murine model of COPD and explored the roles and mechanisms by which LincR-PPP2R5C regulates IL-1β in macrophages. LincR-PPP2R5C was highly expressed in pulmonary macrophages from COPD-like mice. LincR-PPP2R5C deficiency ameliorated emphysema and pulmonary inflammation, as characterized by reduced IL-1β in macrophages. Unexpectedly, in both lung tissues and macrophages, LincR-PPP2R5C deficiency decreased the expression of the IL-1β protein but not the IL-1β mRNA. Furthermore, we found that LincR-PPP2R5C deficiency increased the level of ubiquitinated IL-1β in macrophages, which was mediated by PP2A activity. Targeting PP2A with FTY720 decreased IL-1β and improved COPD. In conclusion, LincR-PPP2R5C regulates IL-1β ubiquitination by affecting PP2A activity in macrophages, contributing to the airway inflammation and emphysema in a murine model of COPD. PP2A and IL-1β ubiquitination in macrophages might be new therapeutic avenues for COPD therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Tripartite motif-containing protein 13 (TRIM13) directly or indirectly participates in autophagy and apoptosis. However, it remains unclear whether TRIM13 participates in chronic obstructive pulmonary disease (COPD) progression. This study aimed to reveal the molecular mechanisms through which TRIM13 regulates alveolar epithelial cell injury in COPD to provide new molecular targets for COPD treatment., Methods: The TRIM13 expression levels were determined in clinical COPD patients and a rat emphysema model. A cigarette smoke-induced model of endoplasmic reticulum stress (ERS) and endoplasmic reticulum autophagy (ER-phagy) was developed using A549 cells, and the effects of TRIM13 gene overexpression/knockdown on ERS, ER-phagy, and cell apoptosis were assessed in these cells., Results: TRIM13 expression was significantly decreased in the lung tissues of COPD patients and rats with emphysema. Moreover, the apoptosis level was significantly increased in the lung tissues of rats with emphysema. TRIM13 gene overexpression reduced the expression levels of ERS-related molecules (GRP78, GRP94, XBP-1, and eIF2a) in the COPD model; it also lowered the ER-phagy level, as evidenced by decreased number of autolysosomes observed by transmission electron microscopy, improved endoplasmic reticulum structure, reduced LC3-II/LC3-I and Beclin1 expression levels, and increased expression level of the autophagy inhibitory molecule Bcl-2. TRIM13 gene knockdown, however, led to opposite results., Conclusion: TRIM13 expression attenuated alveolar epithelial cell injury in COPD by inhibiting ERS-induced ER-phagy., (© 2024. The Author(s).)

Inflammatory cell infiltration is a characteristic feature of COPD and correlates directly with the severity of the disease. Interleukin-23 (IL-23) is a pro-inflammatory cytokine that regulates Th-17 inflammation, which mediates many pathophysiological events in COPD. The primary goal of this study was to determine the role of IL-23 as a mediator of key pathologic processes in cigarette smoke-induced COPD. In this study, we report an increase in IL23 gene expression in the lung biopsies of COPD patients compared to controls and identified a positive correlation between IL23 gene expression and disease severity. In a cigarette smoke-induced murine emphysema model, the suppression of IL-23 with a monoclonal blocking antibody reduced the severity of cigarette smoke-induced murine emphysema. Mechanistically, the suppression of IL-23 was associated with a reduction in immune cell infiltration, oxidative stress injury, and apoptosis, suggesting a role for IL-23 as an essential immune mediator of the inflammatory processes in the pathogenesis of CS-induced emphysema., (© 2024 Wiley Periodicals LLC.)

Purpose: Latent TGF-β binding protein 4 (LTBP4) is involved in the production of elastin fibers and has been implicated in LTBP4-related cutis laxa and its complication, emphysema-like changes. Various factors have been implicated in the pathogenesis of emphysema, including elastic degeneration, inflammation, cellular senescence, mitochondrial dysfunction, and decreased angiogenesis in the lungs. We investigated the association between LTBP4 and emphysema using human lung fibroblasts with silenced LTBP4 genes., Methods: Cell contraction, elastin expression, cellular senescence, inflammation, anti-inflammatory factors, and mitochondrial function were compared between the LTBP4 small interfering RNA (siRNA) and control siRNA., Results: Under the suppression of LTBP4, significant changes were observed in the following: decreased cell contractility, decreased elastin expression, increased expression of the p16 gene involved in cellular senescence, increased TNFα, decreased GSTM3 and SOD, decreased mitochondrial membrane potential, and decreased VEGF expression. Furthermore, the decreased cell contractility and increased GSTM3 expression observed under LTBP4 suppression were restored by the addition of N-acetyl-L-cysteine or recombinant LTBP4., Conclusion: The decreased elastin expression, cellular senescence, inflammation, decreased antioxidant activity, mitochondrial dysfunction, and decreased VEGF expression under reduced LTBP4 expression may all be involved in the destruction of the alveolar wall in emphysema. Smoking is the most common cause of emphysema; however, genetic factors related to LTBP4 expression and other factors may also contribute to its pathogenesis., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2024. Published by Elsevier B.V.)

Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes. We generated an inducible, muscle-specific SDH knockout mouse that demonstrates lower mitochondrial oxygen consumption, myofiber contractility, and exercise endurance. Respirometry analyses show that in vitro complex I respiration is unaffected by loss of SDH subunit C in muscle mitochondria, which is consistent with the pulmonary emphysema animal data. SDH knockout initially causes succinate accumulation associated with a down-regulated transcriptome but modest proteome effects. Muscle mass, myofiber type composition, and overall body mass constituents remain unaltered in the transgenic mice. Thus, while SDH regulates myofiber respiration in experimental pulmonary emphysema, it does not control muscle mass or other body constituents.

Cigarette smoke (CS), an indoor environmental pollutant, is a prominent risk factor for emphysema, which is a pathological feature of chronic obstructive pulmonary disease (COPD). Emerging function of circRNAs in immune responses and disease progression shed new light to explore the pathogenesis of emphysema. In this research, we demonstrated, by single-cell RNA sequencing (scRNAseq), that the ratio of M2 macrophages were increased in lung tissues of humans and mice with smoking-related emphysema. Further, our data showed that circADAMTS6 was associated with cigarette smoke extract (CSE)-induced M2 macrophage polarization. Mechanistically, in macrophages, circADAMTS6 stabilized CAMK2A mRNA via forming a circADAMTS6/IGF2BP2/CAMK2A RNA-protein ternary complex to activate CREB, which drives M2 macrophage polarization and leads to emphysema. In addition, in macrophages of mouse lung tissues, downregulation of circADAMTS6 reversed M2 macrophage polarization, the proteinase/anti-proteinase imbalance, and the elastin degradation, which protecting against CS-induced emphysema. Moreover, for macrophages and in a model with co-cultured lung organoids, the target of circADAMTS6 restored the growth of lung organoids compared to CSE-treated macrophages. Our results also demonstrated that, for smokers and COPD smokers, elevation of circADAMTS6 negatively correlated with lung function. Overall, this study reveals a novel mechanism for circADAMTS6-driven M2 macrophage polarization in smoking-related emphysema and postulates that circADAMTS6 could serve as a diagnostic and therapeutic marker for smoking-related emphysema., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) is a prevalent and preventable condition. Mesenchymal stem cell (MSC) therapy is being explored to aid in the regeneration of lung cells and airway structure, aiming to restore lung function., Aim: To examine varied responses of MSCs when cultured with peripheral blood mononuclear cells (PBMCs) from different COPD phenotypes, patients were grouped into ACOS, emphysema, and chronic bronchitis categories., Methods: PBMCs from these groups and controls were co-cultured with MSCs derived from dental follicles, revealing differing rates of apoptosis among COPD phenotypes compared to controls., Results: While the chronic bronchitis group exhibited the least lymphocyte viability (p<0.01), introducing MSCs notably enhanced viability across all phenotypes except emphysema, with the chronic bronchitis group showing the most improvement (p<0.05)., Conclusion: Stem cell therapy might reduce peripheral lymphocyte apoptosis in COPD, with varying responses based on phenotype, necessitating further research to understand mechanisms and optimize tailored therapies for each COPD subtype., Competing Interests: Declaration of Competing Interest We declare that we have no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Emphysema is generally considered a poor prognostic factor for patients with nonsmall cell lung cancer; however, whether the poor prognosis is due to highly malignant tumors or emphysema itself remains unclear. This study was designed to determine the prognostic value of emphysema in patients with early-stage nonsmall cell lung cancer., Methods: A total of 721 patients with clinical stage IA nonsmall cell lung cancer who underwent complete resection between April 2007 and December 2018 were retrospectively analyzed regarding clinicopathological findings and prognosis related to emphysema., Results: The emphysematous and normal lung groups comprised 197 and 524 patients, respectively. Compared with the normal lung group, lymphatic invasion (23.9% vs. 14.1%, P = 0.003), vascular invasion (37.6% vs. 17.2%, P < 0.001), and pleural invasion (18.8% vs. 10.9%, P = 0.006) were observed more frequently in the emphysema group. Additionally, the 5-year overall survival rate was lower (77.1% vs. 91.4%, P < 0.001), and the cumulative incidence of other causes of death was higher in the emphysema group (14.0% vs. 3.50%, P < 0.001). Multivariable Cox regression analysis of overall survival revealed that emphysema (vs. normal lung, hazard ratio 2.02, P = 0.0052), age > 70 years (vs. < 70 years, hazard ratio 4.03, P < 0.001), and SUVmax > 1.8 (vs. ≤ 1.8, hazard ratio 2.20, P = 0.0043) were independent prognostic factors., Conclusions: Early-stage nonsmall cell lung cancer with emphysema has a tendency for the development of highly malignant tumors. Additionally, emphysema itself may have an impact on poor prognosis., (© 2024. The Author(s).)

Chronic obstructive pulmonary disease (COPD), an inflammatory lung disease, causes approximately 3 million deaths each year; however, its pathological mechanisms are not fully understood. In this study, we examined whether HX110B, a mixture of Taraxacum officinale, Dioscorea batatas, and Schizonepeta tenuifolia extracts, could suppress porcine pancreatic elastase (PPE)-induced emphysema in mice and its mechanism of action. The therapeutic efficacy of HX110B was tested using a PPE-induced emphysema mouse model and human bronchial epithelial cell line BEAS-2B. In vivo data showed that the alveolar wall and air space expansion damaged by PPE were improved by HX110B administration. HX110B also effectively suppresses the expression levels of pro-inflammatory mediators including IL-6, IL-1β, MIP-2, and iNOS, while stimulating the expression of lung protective factors such as IL-10, CC16, SP-D, and sRAGE. Moreover, HX110B improved the impaired OXPHOS subunit gene expression. In vitro analysis revealed that HX110B exerted its effects by activating the PPAR-RXR signaling pathways. Overall, our data demonstrated that HX110B could be a promising therapeutic option for COPD treatment., Competing Interests: All authors are the employees of Helixmith Co., Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic obstructive pulmonary disease (COPD) is a prevalent lung disease usually resulting from cigarette smoking (CS). Cigarette smoking induces oxidative stress, which causes inflammation and alveolar epithelial cell apoptosis and represents a compelling therapeutic target for COPD. Purified human platelet-derived exosome product (PEP) is endowed with antioxidant enzymes and immunomodulatory molecules that mediate tissue repair. In this study, a murine model of CS-induced emphysema was used to determine whether nebulized PEP can influence the development of CS-induced emphysema through the mitigation of oxidative stress and inflammation in the lung. Nebulization of PEP effectively delivered the PEP vesicles into the alveolar region, with evidence of their uptake by type I and type II alveolar epithelial cells and macrophages. Lung function testing and morphometric assessment showed a significant attenuation of CS-induced emphysema in mice treated with nebulized PEP thrice weekly for 4 weeks. Whole lung immuno-oncology RNA sequencing analysis revealed that PEP suppressed several CS-induced cell injuries and inflammatory pathways. Validation of inflammatory cytokines and apoptotic protein expression on the lung tissue revealed that mice treated with PEP had significantly lower levels of S100A8/A9 expressing macrophages, higher levels of CD4+/FOXP3+ Treg cells, and reduced NF-κB activation, inflammatory cytokine production, and apoptotic proteins expression. Further validation using in vitro cell culture showed that pretreatment of alveolar epithelial cells with PEP significantly attenuated CS extract-induced apoptotic cell death. These data show that nebulization of exosomes like PEP can effectively deliver exosome cargo into the lung, mitigate CS-induced emphysema in mice, and suppress oxidative lung injury, inflammation, and apoptotic alveolar epithelial cell death., Competing Interests: Declaration of competing interest A.B., T.P., M.S., and P.S., along with Mayo Clinic, have ownership rights to RION Inc.; C.P. is a scientist employed by Rion Inc. RV has received consulting fees ($10,000) from Rion, Inc and is named as an inventor on a pending international patent #: PCT/US2024/014217)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The antitumor and antimetastatic activity of dopamine D2 receptor antagonists spiperone was studied in C57BL/6 mice in a model of combined pathology (emphysema and lung cancer). Emphysema was induced by administration of LPS and cigarette smoke extract. Lung cancer was induced by injection of Lewis lung carcinoma cells into the lung. It has been shown that under conditions of combined lung pathology, spiperone prevents inflammatory infiltration and emphysematous expansion of the lungs and reduces the size of the primary tumor node, the number of metastases, and the area of the lungs affected by metastases. Spiperone reduces the number of cancer stem cells (CSCs) in the lungs and blood of mice with combined pathology. CSCs isolated from the lungs and blood of mice with combined pathology treated with spiperone had a significantly lower potential to form a tumorosphere in vitro than CSCs from untreated mice with emphysema and lung carcinoma. Thus, blockade of dopamine D2 receptors is a promising approach for correcting combined lung pathology and can be used in the development of a method for treating lung cancer in patients with emphysema., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

The aim of this review is to update and synthesize the molecular mechanisms that lead to the heterogeneous effect on tissue remodeling observed in the two most important clinical phenotypes of chronic obstructive pulmonary disease (COPD), pulmonary emphysema (PE) and chronic bronchitis (CB). Clinical and experimental evidence suggests that this heterogeneous response to promote PE, CB, or both, is related to differentiated genetic, epigenetic, and molecular conditions. Specifically, a tendency toward PE could be related to a variant in the DSP gene, SIRT1 downregulation, macrophage polarization to M1, as well as the involvement of the noncanonical Wnt5A signaling pathway, among other alterations. Additionally, in advanced stages of COPD, PE development is potentiated by dysregulations in autophagy, which promotes senescence and subsequently cell apoptosis, through exacerbated inflammasome activation and release of caspases. On the other hand, CB or the pro-fibrotic phenotype could be potentiated by the downregulated activity of HDAC2, the activation of the TGF-β/Smad or Wnt/β-catenin signaling pathways, macrophage polarization to M2, upregulation of TIMP-1, and/or the presence of the epithelial-mesenchymal transition (EMT) mechanism. Interestingly, the upregulated activity of MMPs, especially MMP-9, is widely involved in the development of both phenotypes. Furthermore, MMP-9 and MMP-12 enhance the severity, perpetuation, and exacerbation of COPD, as well as the development of autoimmunity in this disease., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

In chronic obstructive pulmonary disease (COPD), inflammation gives rise to protease-mediated degradation of the key extracellular matrix protein, elastin, which causes irreversible loss of pulmonary function. Intervention against proteolysis has met with limited success in COPD, due in part to our incomplete understanding of the mechanisms that underlie disease pathogenesis. Peptidyl arginine deiminase (PAD) enzymes are a known modifier of proteolytic susceptibility, but their involvement in COPD in the lungs of affected individuals is underexplored. In this study, we showed that enzyme isotypes PAD2 and PAD4 are present in primary granules of neutrophils and that cells from people with COPD release increased levels of PADs when compared with neutrophils of healthy control subjects. By examining bronchoalveolar lavage and lung tissue samples of patients with COPD or matched smoking and nonsmoking counterparts with normal lung function, we reveal that COPD presents with markedly increased airway concentrations of PADs. Ex vivo, we established citrullinated elastin in the peripheral airways of people with COPD, and in vitro, elastin citrullination significantly enhanced its proteolytic degradation by serine and matrix metalloproteinases, including neutrophil elastase and matrix metalloprotease-12, respectively. These results provide a mechanism by which neutrophil-released PADs affect lung function decline, indicating promise for the future development of PAD-based therapeutics for preserving lung function in patients with COPD., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Senescent cells contribute to tissue aging and underlie the pathology of chronic diseases. The benefits of eliminating senescent cells have been demonstrated in several disease models, and the efficacy of senolytic drugs is currently being tested in humans. Exercise training has been shown to reduce cellular senescence in several tissues; however, the mechanisms responsible remain unclear. We found that myocyte-derived factors significantly extended the replicative lifespan of fibroblasts, suggesting that myokines mediate the anti-senescence effects of exercise. A number of proteins within myocyte-derived factors were identified by mass spectrometry. Among these, pigment epithelium-derived factor (PEDF) exerted inhibitory effects on cellular senescence. Eight weeks of voluntary running increased Pedf levels in skeletal muscles and suppressed senescence markers in the lungs. The administration of PEDF reduced senescence markers in multiple tissues and attenuated the decline in respiratory function in the pulmonary emphysema mouse model. We also showed that blood levels of PEDF inversely correlated with the severity of COPD in patients. Collectively, these results strongly suggest that PEDF contributes to the beneficial effects of exercise, potentially suppressing cellular senescence and its associated pathologies.

Cigarette smoking is known to be the leading cause of chronic obstructive pulmonary disease (COPD). However, the detailed mechanisms have not been elucidated. PAF (platelet-activating factor), a potent inflammatory mediator, is involved in the pathogenesis of various respiratory diseases such as bronchial asthma and COPD. We focused on LPLAT9 (lysophospholipid acyltransferase 9), a biosynthetic enzyme of PAF, in the pathogenesis of COPD. LPLAT9 gene expression was observed in excised COPD lungs and single-cell RNA sequencing data of alveolar macrophages (AMs). LPLAT9 was predominant and upregulated in AMs, particularly monocyte-derived AMs, in patients with COPD. To identify the function of LPLAT9/PAF in AMs in the pathogenesis of COPD, we exposed systemic LPLAT9-knockout (LPALT9 -/- ) mice to cigarette smoke (CS). CS increased the number of AMs, especially the monocyte-derived fraction, which secreted MMP12 (matrix metalloprotease 12). Also, CS augmented LPLAT9 phosphorylation/activation on macrophages and, subsequently, PAF synthesis in the lung. The LPLAT9 -/- mouse lung showed reduced PAF production after CS exposure. Intratracheal PAF administration accumulated AMs by increasing MCP1 (monocyte chemoattractant protein-1). After CS exposure, AM accumulation and subsequent pulmonary emphysema, a primary pathologic change of COPD, were reduced in LPALT9 -/- mice compared with LPLAT9 +/+ mice. Notably, these phenotypes were again worsened by LPLAT9 +/+ bone marrow transplantation in LPALT9 -/- mice. Thus, CS-induced LPLAT9 activation in monocyte-derived AMs aggravated pulmonary emphysema via PAF-induced further accumulation of AMs. These results suggest that PAF synthesized by LPLAT9 has an important role in the pathogenesis of COPD.

Irreversible alveolar airspace enlargement is the main characteristic of pulmonary emphysema, which has been extensively studied using animal models. While the alterations in lung mechanics associated with these morphological changes have been documented in the literature, the study of the mechanical behavior of parenchymal tissue from emphysematous lungs has been poorly investigated. In this work, we characterize the mechanical and morphological properties of lung tissue in elastase-induced emphysema rat models under varying severity conditions. We analyze the non-linear tissue behavior using suitable hyperelastic constitutive models that enable to compare different non-linear responses in terms of hyperelastic material parameters. We further analyze the effect of the elastase dose on alveolar morphology and tissue material parameters and study their connection with respiratory-system mechanical parameters. Our results show that while the lung mechanical function is not significantly influenced by the elastase treatment, the tissue mechanical behavior and alveolar morphology are markedly affected by it. We further show a strong association between alveolar enlargement and tissue softening, not evidenced by respiratory-system compliance. Our findings highlight the importance of understanding tissue mechanics in emphysematous lungs, as changes in tissue properties could detect the early stages of emphysema remodeling. STATEMENT OF SIGNIFICANCE: Gas exchange is vital for life and strongly relies on the mechanical function of the lungs. Pulmonary emphysema is a prevalent respiratory disease where alveolar walls are damaged, causing alveolar enlargement that induces harmful changes in the mechanical response of the lungs. In this work, we study how the mechanical properties of lung tissue change during emphysema. Our results from animal models show that tissue properties are more sensitive to alveolar enlargement due to emphysema than other mechanical properties that describe the function of the whole respiratory system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Indium lung is an occupational lung disease caused by exposure to indium-tin-oxide (ITO) dust. Compared to other occupational lung diseases, indium lung has a shorter latency period and the respiratory status continues to worsen even after exposure to the work environment improves. Paraseptal emphysema which affects mainly the subpleural area is seen on chest images obtained via computed tomography (CT), regardless of the smoking history. However, the pathogenesis of emphysema in indium lung is still unclear. Therefore, we re-evaluated the pathology of three previously reported cases of indium lung. Paraseptal emphysema was observed in both smokers and nonsmokers. Obstructive respiratory impairment worsened over time in the cases with paraseptal emphysema. Many alveolar walls were destroyed independent of the presence or absence of emphysetamous changes or fibrosis. Moreover, bronchiolitis was found to be less common in indium lung than in asbestosis (the most common occupational lung disease) or common cases of chronic obstructive pulmonary disease caused by smoking. It has been shown that ITO causes protease anti-protease imbalance, oxidant-antioxidant imbalance, and continuous, abnormal inflammation (the three major causes of emphysema). In addition, nano-sized ITO is less likely to be trapped in the upper airways and may easily reach the subpleural alveoli. Furthermore, ITO may continue to cause sustained tissue injury at the alveolar level potentially resulting in emphysema. Further studies are needed to elucidate the detailed pathogenesis of indium lung by comparing it with other occupational lung diseases.

Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 microRNA ( Mirlet7 miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the Mirlet7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here, we show that overall expression of the Mirlet7 clusters, Mirlet7b/Mirlet7c2 and Mirlet7a1/Mirlet7f1/Mirlet7d , are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)- or nCB-elicited emphysema. We demonstrate that loss of the Mirlet7b/Mirlet7c2 cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the Mirlet7b/Mirlet7c2 cluster enhanced CD8 + IL17a + T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing Mirlet7g in T cells are resistant to Tc17 and CD4 + IL17a + T cells (Th17) development when exposed to nCB. Mechanistically, our findings reveal the master regulator of Tc17/Th17 differentiation, RAR-related orphan receptor gamma t (RORγt), as a direct target of Mirlet7 in T cells. Overall, our findings shed light on the Mirlet7/ RORγt axis with Mirlet7 acting as a molecular brake in the generation of Tc17 cells and suggest a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema., Competing Interests: PE, XH, MS, MR, HT, MP, SL, DC, FK, AR No competing interests declared, (© 2024, Erice et al.)

Rationale: Small airway disease is an important pathophysiological feature of chronic obstructive pulmonary disease (COPD). Recently, "pre-COPD" has been put forward as a potential precursor stage of COPD that is defined by abnormal spirometry findings or significant emphysema on computed tomography (CT) in the absence of airflow obstruction. Objective: To determine the degree and nature of (small) airway disease in pre-COPD using microCT in a cohort of explant lobes/lungs. Methods: We collected whole lungs/lung lobes from patients with emphysematous pre-COPD ( n  = 10); Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I ( n  = 6), II ( n  = 6), and III/IV ( n  = 7) COPD; and controls ( n  = 10), which were analyzed using CT and microCT. The degree of emphysema and the number and morphology of small airways were compared between groups, and further correlations were investigated with physiologic measures. Airway and parenchymal pathology was also validated with histopathology. Measurements and Main Results: The numbers of transitional bronchioles and terminal bronchioles per milliliter of lung were significantly lower in pre-COPD and GOLD stages I, II, and III/IV COPD compared with controls. In addition, the number of alveolar attachments of the transitional bronchioles and terminal bronchioles was also lower in pre-COPD and all COPD groups compared with controls. We did not find any differences between the pre-COPD and COPD groups in CT or microCT measures. The percentage of emphysema on CT showed the strongest correlation with the number of small airways in the COPD groups. Histopathology showed an increase in the mean chord length and a decrease in alveolar surface density in pre-COPD and all GOLD COPD stages compared with controls. Conclusions: Lungs of patients with emphysematous pre-COPD already show fewer small airways and airway remodeling even in the absence of physiologic airway obstruction.

Ethnopharmacological Relevance: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory respiratory disease. Citrus Reticulata peel, the dried ripe peel of Citrus Reticulata species, has been found to have anti-inflammatory and cough attenuation effects. However, the therapeutic effects and its precise underlying mechanisms of atomizing inhalation using Citrus Reticulata essential oil (CREO) have not yet been fully elucidated., Aim of the Study: The aim of this study was to assess the therapeutic effects of Citrus Reticulata essential oil and its associated anti-inflammatory mechanisms in COPD rat model., Methods: A total of 80 SD rats were randomized into four groups: control group (Con), COPD model group (COPD), COPD + ipratropium bromide (IB), and COPD + citrus reticulata essential oil (CREO). To induce COPD in rats, cigarette smoke (CS) exposure was used, while CREO and IB groups were administered through atomizing inhalation. The clinical signs, pathological lesions of the lung, percentages of antigen-presenting lung macrophages (CD11b/c + /CD86 + cells) and CD8 + T cells, and the content and mRNA expression of cytokines of the lung were analyzed., Results: The findings revealed that atomizing inhalation of Citrus reticulata essential oil had therapeutic effects on COPD rats. The treatment resulted in improvement in the body weight and mental status of COPD rats, reduced pathological injury of the lung, and increased proportion of CD11b/c + /CD86 + cells in lung macrophages, while also decreasing the number of CD8 + T cells. In addition, the Citrus Reticulata essential oil reduced the contents of IL-18, IL-17A, IL-12p70, and GM-CSF, downregulated the relative mRNA expression of IFN-γ, IL-4, and MMP-12, and upregulated the mRNA expression of IL-10., Conclusions: Citrus reticulata essential oil can alleviate histological injury of the lung and regulate macrophages and CD8 + T cells in COPD rats. The study suggests that citrus reticulata essential oil could be a potential therapeutic agent for COPD., Competing Interests: Declaration of competing interest Xi Peng and Qiaobo Ye: Conceptualization, Supervision, Project administration and Funding acquisition. Qing Deng and Juan Wang: Methodology and Investigation. Zhengqiang Yu, Jiajia Deng, Zhenhua Sun, Zhen Ye and Kaihua Qin:Resources. Changlin Wen and Zhengqiang Yu:Investigation and Formal analysis. Xi Peng, Changlin Wen, Zhengqiang Yu and Qiaobo Ye andWriting - Original Draft and Visualization. All authors contributed to perform the fundamental experiments and approve the final submitted version of the manuscript. All the authors report no conflicts of interest in this work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: The present study evaluated the sex-specific susceptibility to the development of emphysema in patients with smoking histories who underwent lung cancer surgeries., Methods: Lung cancer patients with smoking histories who underwent lung resection at the University of Tsukuba Hospital, Japan, were enrolled. Radiologic emphysematous changes were analyzed using three-dimensional computed tomography (3D-CT). The volume proportion of emphysematous lung per unit of smoking and the relationship between emphysematous change and clinicopathologic factors were evaluated., Results: Radiologic emphysematous changes analyzed using 3D-CT per pack-year smoked, defined as the Smoking-Emphysema Index (SEI), were greater in females than males. The difference was more profound in adenocarcinoma patients than in non-adenocarcinoma patients (0.70 ± 2.30 vs. 0.21 ± 0.28, P = 0.037)., Conclusion: Female lung cancer patients are more susceptible to smoking-induced emphysema than males. The SEI may be an effective indicator for evaluating smoking-induced emphysema., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Increasing evidence indicates that bioactive lipid mediators are involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Recently, glycero-lysophospholipids, such as lysophosphatidic acid (LysoPA) and lysophosphatidylserine (LysoPS), have been recognized as significant inflammation-related lipid mediators. However, their association with COPD remains unclear., Methods: We used an elastase-induced murine emphysema model to analyze the levels of lysophospholipids and diacyl-phospholipids in the lungs. Additionally, we assessed the expression of LysoPS-related genes and published data on smokers., Results: In the early phase of an elastase-induced murine emphysema model, the levels of LysoPS and its precursor (phosphatidylserine [PS]) were significantly reduced, without significant modulations in other glycero-lysophospholipids. Additionally, there was an upregulation in the expression of lysoPS receptors, specifically GPR34, observed in the lungs of a cigarette smoke-exposed mouse model and the alveolar macrophages of human smokers. Elastase stimulation induces GPR34 expression in a human macrophage cell line in vitro., Conclusions: Elastase-induced lung emphysema affects the LysoPS/PS-GPR34 axis, and cigarette smoking or elastase upregulates GPR34 expression in alveolar macrophages. This novel association may serve as a potential pharmacological target for COPD treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Smoking is a leading risk factor of chronic obstructive pulmonary disease (COPD), that is characterized by chronic lung inflammation, tissue remodeling and emphysema. Although inflammation is critical to COPD pathogenesis, the cellular and molecular basis underlying smoking-induced lung inflammation and pathology remains unclear. Using murine smoke models and single-cell RNA-sequencing, we show that smoking establishes a self-amplifying inflammatory loop characterized by an influx of molecularly heterogeneous neutrophil subsets and excessive recruitment of monocyte-derived alveolar macrophages (MoAM). In contrast to tissue-resident AM, MoAM are absent in homeostasis and characterized by a pro-inflammatory gene signature. Moreover, MoAM represent 46% of AM in emphysematous mice and express markers causally linked to emphysema. We also demonstrate the presence of pro-inflammatory and tissue remodeling associated MoAM orthologs in humans that are significantly increased in emphysematous COPD patients. Inhibition of the IRAK4 kinase depletes a rare inflammatory neutrophil subset, diminishes MoAM recruitment, and alleviates inflammation in the lung of cigarette smoke-exposed mice. This study extends our understanding of the molecular signaling circuits and cellular dynamics in smoking-induced lung inflammation and pathology, highlights the functional consequence of monocyte and neutrophil recruitment, identifies MoAM as key drivers of the inflammatory process, and supports their contribution to pathological tissue remodeling., Competing Interests: Author FG was employed by company C. H. Boehringer Sohn AG & Co. KG. CW, CWa, YS, GL, CT, FH, DK, BS, DD, CV, and PB were employed by Boehringer Ingelheim Pharma GmbH & Co. KG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Wohnhaas, Baßler, Watson, Shen, Leparc, Tilp, Heinemann, Kind, Stierstorfer, Delić, Brunner, Gantner, Schultze, Viollet and Baum.)

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease with no effective treatment that can reduce mortality or slow the disease progression. COPD is the third leading cause of global death and is characterized by airflow limitations due to chronic bronchitis and alveolar damage/emphysema. Chronic cigarette smoke (CS) exposure damages airway and alveolar epithelium and remains a major risk factor for the pathogenesis of COPD. We found that the expression of caveolin-1, a tumor suppressor protein; p53; and plasminogen activator inhibitor-1 (PAI-1), one of the downstream targets of p53, was markedly increased in airway epithelial cells (AECs) as well as in type II alveolar epithelial (AT2) cells from the lungs of patients with COPD or wild-type mice with CS-induced lung injury (CS-LI). Moreover, p53- and PAI-1-deficient mice resisted CS-LI. Furthermore, treatment of AECs, AT2 cells, or lung tissue slices from patients with COPD or mice with CS-LI with a seven amino acid caveolin-1 scaffolding domain peptide (CSP7) reduced mucus hypersecretion in AECs and improved AT2 cell viability. Notably, induction of PAI-1 expression via increased caveolin-1 and p53 contributed to mucous cell metaplasia and mucus hypersecretion in AECs, and reduced AT2 viability, due to increased senescence and apoptosis, which was abrogated by CSP7. In addition, treatment of wild-type mice having CS-LI with CSP7 by intraperitoneal injection or nebulization via airways attenuated mucus hypersecretion, alveolar injury, and significantly improved lung function. This study validates the potential therapeutic role of CSP7 for treating CS-LI and COPD. NEW & NOTEWORTHY Chronic cigarette smoke (CS) exposure remains a major risk factor for the pathogenesis of COPD, a debilitating disease with no effective treatment. Increased caveolin-1 mediated induction of p53 and downstream plasminogen activator inhibitor-1 (PAI-1) expression contributes to CS-induced airway mucus hypersecretion and alveolar wall damage. This is reversed by caveolin-1 scaffolding domain peptide (CSP7) in preclinical models, suggesting the therapeutic potential of CSP7 for treating CS-induced lung injury (CS-LI) and COPD.

Background: Hypomethylation of the perforin gene promoter in CD4 + T cells, inflammation and oxidative stress, might be involved in alveolar septal cell apoptosis associated with emphysema in rats. This study aimed to investigate the effects of S-adenosylmethionine (SAM) on this kind of apoptosis in rats with autoimmune emphysema., Methods: Twenty-four rats were randomly divided into three groups: a normal control group, a model group, and a SAM group. Pathological changes in lung tissues were observed, and the mean linear intercept (MLI) and mean alveolar number (MAN) were measured. The levels of anti-endothelial cell antibodies (AECA) in serum, alveolar septal cell apoptosis, perforin gene promotor methylation in CD4 + T cells in the spleen, and the levels of cytokines, malondialdehyde (MDA), and glutathione (GSH) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in bronchoalveolar lavage fluid (BALF) were investigated., Results: The MLI, apoptosis index (AI) of alveolar septal cells, levels of AECA in serum, and levels of tumour necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9) and MDA in BALF were increased, while the MAN, methylation levels, and the activities of GSH, SOD and GSH-Px in BALF were decreased in the model group compared with those in the normal control group and the SAM group (all P < 0.05). The levels of interleukin-8 (IL-8) in BALF were greater in the model group than in the normal control group (P < 0.05)., Conclusions: SAM protects against alveolar septal cell apoptosis, airway inflammation and oxidative stress in rats with autoimmune emphysema possibly by partly reversing the hypomethylation of the perforin gene promoter in CD4 + T cells., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Type 1 diabetes (T1D) is a metabolic disease characterized by hyperglycemia and can affect multiple organs, leading to life-threatening complications. Increased prevalence of pulmonary disease is observed in T1D patients, and diabetes is a leading cause of comorbidity in several lung pathologies. A deficiency of alpha-1 antitrypsin (AAT) can lead to the development of emphysema. Decreased AAT plasma concentrations and anti-protease activity are documented in T1D patients. The objective of this study was to determine whether T1D exacerbates the progression of lung damage in AAT deficiency. First, pulmonary function testing (PFT) and histopathological changes in the lungs of C57BL/6J streptozotocin (STZ)-induced T1D mice were investigated 3 and 6 months after the onset of hyperglycemia. PFT demonstrated a restrictive pulmonary pattern in the lungs of STZ-injected mice, along with upregulation of mRNA expression of pro-fibrotic markers Acta2, Ccn2, and Fn1. Increased collagen deposition was observed 6 months after the onset of hyperglycemia. To study the effect of T1D on the progression of lung damage in AAT deficiency background, C57BL/6J AAT knockout (KO) mice were used. Control and STZ-challenged AAT KO mice did not show significant changes in lung function 3 months after the onset of hyperglycemia. However, histological examination of the lung demonstrated increased collagen accumulation and alveolar space enlargement in STZ-induced AAT KO mice. AAT pretreatment on TGF-β-stimulated primary lung fibroblasts reduced mRNA expression of pro-fibrotic markers ACTA2, CCN2, and FN1. Induction of T1D in AAT deficiency leads to a combined pulmonary fibrosis and emphysema (CPFE) phenotype in male mice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Park et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic obstructive pulmonary disease (COPD) is a clinical entity of increasing significance. COPD involves abnormalities of the airways and, in emphysema, parenchymal pulmonary destruction. Cardiovascular disease has emerged as a significant comorbidity to COPD. Heart failure with preserved ejection fraction (HFpEF) appears to be particularly associated with COPD-emphysema. Traditional treatments have shown limited efficacy in improving COPD-associated HFpEF. This lack of therapeutic efficacy highlights the need to identify potential mechanisms that link COPD-emphysema to HFpEF. Therefore, we aimed to study the delayed cardiac physiological impacts in a rat model with acute exacerbated emphysema. Emphysema was induced by four weekly 4 units elastase (ELA) intratracheal pulmonary instillations and exacerbation by one final additional lipolysaccharide (LPS) instillation in male Wistar rats. At 5 weeks after the ELA and LPS exposure, in vivo and ex vivo pulmonary and cardiac measurements were performed. Experimental exacerbated emphysema resulted in decreased pulmonary function and exercise intolerance. Histological analysis revealed parenchymal pulmonary destruction without signs of inflammation or cardiac fibrosis. In vivo cardiac functional analysis revealed diastolic dysfunction and tachycardia. Ex vivo analysis revealed a cellular cardiomyopathy with decreased myofilament Ca 2+ sensitivity, cross-bridge cycling kinetics, and increased adrenergic PKA (protein kinase A)-dependent phosphorylation of troponin-I. Experimental exacerbated emphysema was associated with exercise intolerance that appeared to be secondary to increased β-adrenergic tone and subsequent cardiac myofilament dysfunction. A β 1 -receptor antagonist treatment (bisoprolol) started 24 hours after ELA-LPS instillation prevented in vivo and ex vivo diastolic dysfunction. These results suggest that novel treatment strategies targeted to the cardiac myofilament may be beneficial to combat exacerbated emphysema-associated HFpEF.

Cigarette smoke (CS) leads to increased oxidative stress, inflammation, and exaggerated senescence, which are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). While the role of cellular senescence in COPD is known, it is not clear if the removal of senescent cells could alleviate the disease symptoms. To test this, we used the novel mouse model-p16-3MR, and studied the effect of ganciclovir (GCV)-mediated removal of senescent cells after chronic CS (3 months) and environmental tobacco smoke (ETS) (6 months) exposure to CS. Our results showed the reversal of CS-induced cellular senescence on the clearance of p16 + senesced cells by GCV treatment. Interestingly, the clearance of p16 + senescent cells via GCV led to a decrease in the neutrophil counts in the BALF of GCV-treated CS-exposed p16-3MR mice, as well as reversal of CS-mediated airspace enlargement in p16-3MR mice. Mice exposed to low dose ETS caused insignificant changes in the SA-β-Gal + senescent cells and airspace enlargement. Overall, our data provide evidence for the role of lung cellular senescence on smoke exposure and clearance of senescent cells in p16-3MR mice in the reversal of COPD/emphysema pathology with a possibility of senolytics as therapeutic interventions in COPD., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Objectives: Pulmonary emphysema is characterized by the destruction of alveolar units and reduced gas exchange capacity. In the present study, we aimed to deliver induced pluripotent stem cell-derived endothelial cells and pneumocytes to repair and regenerate distal lung tissue in an elastase-induced emphysema model., Methods: We induced emphysema in athymic rats via intratracheal injection of elastase as previously reported. At 21 and 35 days after elastase treatment, we suspended 80 million induced pluripotent stem cell-derived endothelial cells and 20 million induced pluripotent stem cell-derived pneumocytes in hydrogel and injected the mixture intratracheally. On day 49 after elastase treatment, we performed imaging, functional analysis, and collected lungs for histology., Results: Using immunofluorescence detection of human-specific human leukocyte antigen 1, human-specific CD31, and anti--green fluorescent protein for the reporter labeled pneumocytes, we found that transplanted cells engrafted in 14.69% ± 0.95% of the host alveoli and fully integrated to form vascularized alveoli together with host cells. Transmission electron microscopy confirmed the incorporation of the transplanted human cells and the formation of a blood-air barrier. Human endothelial cells formed perfused vasculature. Computed tomography scans revealed improved vascular density and decelerated emphysema progression in cell-treated lungs. Proliferation of both human and rat cell was higher in cell-treated versus nontreated controls. Cell treatment reduced alveolar enlargement, improved dynamic compliance and residual volume, and improved diffusion capacity., Conclusions: Our findings suggest that human induced pluripotent stem cell-derived distal lung cells can engraft in emphysematous lungs and participate in the formation of functional distal lung units to ameliorate the progression of emphysema., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Congenital lobar emphysema (CLE) is a rare developmental lung disorder characterized by lobar hyperinflation secondary to bronchopulmonary obstruction. Half of patients are symptomatic at birth, with many requiring urgent or emergent surgical resection to treat respiratory distress. Meanwhile, patients achieving late childhood or adolescence without symptoms usually never require surgery. We present a case of a 26 year old otherwise healthy female with known CLE who developed massive hemoptysis and required urgent videoscopic (VATS) resection of her right lung upper lobe. We know of no other report of CLE causing life-threatening bleeding at any age, and herein review pathology and pathophysiology of the condition.

Objectives: To assess the value of quantitative computed tomography (QCT) of the whole lung and nodule-bearing lobe regarding pulmonary nodule malignancy risk estimation., Methods: A total of 251 subjects (median [IQR] age, 65 (57-73) years; 37% females) with pulmonary nodules on non-enhanced thin-section CT were retrospectively included. Twenty percent of the nodules were malignant, the remainder benign either histologically or at least 1-year follow-up. CT scans were subjected to in-house software, computing parameters such as mean lung density (MLD) or peripheral emphysema index (pEI). QCT variable selection was performed using logistic regression; selected variables were integrated into the Mayo Clinic and the parsimonious Brock Model., Results: Whole-lung analysis revealed differences between benign vs. malignant nodule groups in several parameters, e.g. the MLD (-766 vs. -790 HU) or the pEI (40.1 vs. 44.7 %). The proposed QCT model had an area-under-the-curve (AUC) of 0.69 (95%-CI, 0.62-0.76) based on all available data. After integrating MLD and pEI into the Mayo Clinic and Brock Model, the AUC of both clinical models improved (AUC, 0.91 to 0.93 and 0.88 to 0.91, respectively). The lobe-specific analysis revealed that the nodule-bearing lobes had less emphysema than the rest of the lung regarding benign (EI, 0.5 vs. 0.7 %; p < 0.001) and malignant nodules (EI, 1.2 vs. 1.7 %; p = 0.001)., Conclusions: Nodules in subjects with higher whole-lung metrics of emphysema and less fibrosis are more likely to be malignant; hereby the nodule-bearing lobes have less emphysema. QCT variables could improve the risk assessment of incidental pulmonary nodules., Key Points: • Nodules in subjects with higher whole-lung metrics of emphysema and less fibrosis are more likely to be malignant. • The nodule-bearing lobes have less emphysema compared to the rest of the lung. • QCT variables could improve the risk assessment of incidental pulmonary nodules., (© 2022. The Author(s).)

Combined pulmonary fibrosis and emphysema (CPFE) is a recently recognized syndrome that, as its name indicates, involves the existence of both interstitial lung fibrosis and emphysema in one individual, and is often accompanied by pulmonary hypertension. This debilitating, progressive condition is most often encountered in males with an extensive smoking history, and is presented by dyspnea, preserved lung volumes, and contrastingly impaired gas exchange capacity. The diagnosis of the disease is based on computed tomography imaging, demonstrating the coexistence of emphysema and interstitial fibrosis in the lungs, which might be of various types and extents, in different areas of the lung and several relative positions to each other. CPFE bears high mortality and to date, specific and efficient treatment options do not exist. In this review, we will summarize current knowledge about the clinical attributes and manifestations of CPFE. Moreover, we will focus on pathophysiological and pathohistological lung phenomena and suspected etiological factors of this disease. Finally, since there is a paucity of preclinical research performed for this particular lung pathology, we will review existing animal studies and provide suggestions for the development of additional in vivo models of CPFE syndrome.

Placental transmogrification of the lung (PTL) is a very rare benign lung lesion. There are only about 40 cases reported in the literature. The imaging and histological features of PTL cases in the publication are various, most of which are cystic and a few of which are solid. Being extremely rare, the solid PTL is unknown to major pathologists and surgeons. We reported a case of solid PTL in the anterior mediastinum. The patient was a 52-year-old male with no history of smoking and without symptoms. During physical examination, chest CT revealed a circular low-density lesion with a maximum diameter of 2.9 cm beside the spine in the posterior basal segment of the left lower lobe of the lung. The wedge resection was performed by video-assisted thoracoscopy. Grossly, a round nodule was located underneath the visceral pleura. It was about 3.0 cm×3.0 cm×1.6 cm and the cut surface was grey-red, soft and spongy. Microscopically, the nodule was constituted of papillare, which resembled placental villi at low magnification. The axis of papillae was edema, in which some mild round cells with clear cytoplasm and CD10 positive staining aggregated and transitioned to immature adipocytes and amorphous pink materials deposited with a few of inflammatory cells infiltration. The surface of papillae was covered with disconti-nuous alveolar epithelium. Combined with the typical morphology and immunohistochemical characteristics of CD10 positive, the diagnosis was PTL. The patient was followed up for 1 year without recurrence and discomfort. So far, the pathogenesis of PTL is unclear. The major hypotheses include hamartoma, variant of emphysema and clonal hyperplasia of stromal cells. Based on the study of our case and publication, we speculate that the hyperplasia of stromal cells located in the alveolar septa might be the first step to form the solid PTL. With the progression of the disease, a typical unilateral cystic nodule develops as a result of secondary cystic degeneration due to the occlusive valve effect. Surgery is the only option for diagnosis and treatment of PTL. The clinician should make an individualized operation plan according to the clinical manifestations, location and scope of the lesion, and preserve the surrounding normal lung tissue as much as possible while completely removing the lesion. There is a favorable prognosis.

The pathophysiology of chronic obstructive pulmonary disease (COPD) and the undisputed role of innate immune cells in this condition have dominated the field in the basic research arena for many years. Recently, however, compelling data suggesting that adaptive immune cells may also contribute to the progressive nature of lung destruction associated with COPD in smokers have gained considerable attention. The histopathological changes in the lungs of smokers can be limited to the large or small airways, but alveolar loss leading to emphysema, which occurs in some individuals, remains its most significant and irreversible outcome. Critically, however, the question of why emphysema progresses in a subset of former smokers remained a mystery for many years. The recognition of activated and organized tertiary T- and B-lymphoid aggregates in emphysematous lungs provided the first clue that adaptive immune cells may play a crucial role in COPD pathophysiology. Based on these findings from human translational studies, experimental animal models of emphysema were used to determine the mechanisms through which smoke exposure initiates and orchestrates adaptive autoreactive inflammation in the lungs. These models have revealed that T helper (Th)1 and Th17 subsets promote a positive feedback loop that activates innate immune cells, confirming their role in emphysema pathogenesis. Results from genetic studies and immune-based discoveries have further provided strong evidence for autoimmunity induction in smokers with emphysema. These new findings offer a novel opportunity to explore the mechanisms underlying the inflammatory landscape in the COPD lung and offer insights for development of precision-based treatment to halt lung destruction.

Background: The purpose of this study was to examine the relationship between the lobar emphysema ratio (LER) and tumor recurrence and survival in patients with stage I non-small cell lung cancer (NSCLC)., Methods: We enrolled 258 patients with surgically proven stage I NSCLC. These patients underwent noncontrast chest CT, and pulmonary lobe segmentation and lobar emphysema quantification were performed using commercially available software. We assessed the LER in the lobe with lung cancer. We divided the patients into two groups according to the LER, and the cut-off value was 1. Furthermore, we analyzed the disease-free survival of high LER and other clinical factors after surgical resection., Results: The 258 patients were divided into two groups: low LER (n = 195) and high LER (n = 63). The right upper lobe was the most frequent location in lung cancer and the most severe location in emphysema. In the Kaplan‒Meier curve, high LER showed a significantly lower disease-free survival (8.21 ± 0.27 years vs 6.53 ± 0.60 years, p = 0.005) and overall survival (9.56 ± 0.15 years vs. 8.51 ± 0.49 years, p = 0.011) than low LER. Stage Ib (2.812 [1.661-4.762], p<0.001) and high LER (2.062 [1.191-3.571], p = 0.010) were poor predictors for disease-free survival in multivariate Cox regression analysis. Stage Ib (4.729 [1.674-13.356], p = 0.003) and high LER (3.346 [1.208-9.269], p = 0.020) were significant predictors for overall survival in multivariate Cox regression analysis., Conclusion: A LER of more than 1% in the lobe with lung cancer is a poor predictor for cancer recurrence and overall survival in patients with stage I NSCLC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterised by airflow limitation, chronic bronchitis, emphysema and airway remodelling. Cigarette smoke is considered the primary risk factor for the development of COPD; however, genetic factors, host responses and infection also play an important role. Accumulating evidence highlights a role for iron dyshomeostasis and cellular iron accumulation in the lung as a key contributing factor in the development and pathogenesis of COPD. Recent studies have also shown that mitochondria, the central players in cellular iron utilisation, are dysfunctional in respiratory cells in individuals with COPD, with alterations in mitochondrial bioenergetics and dynamics driving disease progression. Understanding the molecular mechanisms underlying the dysfunction of mitochondria and cellular iron metabolism in the lung may unveil potential novel investigational avenues and therapeutic targets to aid in the treatment of COPD., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The development of new drugs for idiopathic pulmonary fibrosis strongly relies on preclinical experimentation, which requires the continuous improvement of animal models and integration with in vivo imaging data. Here, we investigated the lung distribution of bleomycin (BLM) associated with the indocyanine green (ICG) dye by fluorescence imaging. A long-lasting lung retention (up to 21 days) was observed upon oropharyngeal aspiration (OA) of either ICG or BLM + ICG, with significantly more severe pulmonary fibrosis, accompanied by the progressive appearance of emphysema-like features, uniquely associated with the latter combination. More severe and persistent lung fibrosis, together with a progressive air space enlargement uniquely associated with the BLM + ICG group, was confirmed by longitudinal micro-computed tomography (CT) and histological analyses. Multiple inflammation and fibrosis biomarkers were found to be increased in the bronchoalveolar lavage fluid of BLM- and BLM + ICG-treated animals, but with a clear trend toward a much stronger increase in the latter group. Similarly, in vitro assays performed on macrophage and epithelial cell lines revealed a significantly more marked cytotoxicity in the case of BLM + ICG-treated mice. Also unique to this group was the synergistic upregulation of apoptotic markers both in lung sections and cell lines. Although the exact mechanism underlying the more intense lung fibrosis phenotype with emphysema-like features induced by BLM + ICG remains to be elucidated, we believe that this combination treatment, whose overall effects more closely resemble the human disease, represents a valuable alternative model for studying fibrosis development and for the identification of new antifibrotic compounds.

Introduction: Chronic obstructive pulmonary disease (COPD) has high morbidity and mortality, with no effective treatment at present. Emphysema, a major component of COPD, is a leading cause of human death worldwide. Fibroblast growth factor 2 (FGF2) is implicated in the pathogenesis of pulmonary emphysema and may play an important role in the lung repair process after injury, but concerns remain with respect to its effectiveness., Objective: In the present work, we sought to determine how the timing (early and late intervention) of sustained-release FGF2 system administration impacted its effectiveness on a porcine pancreatic elastase (PPE)-induced lung injury mouse model., Methods: To examine the early intervention efficiency of collagen-binding FGF2 (CBD-FGF2), mice received intratracheally nebulized CBD-FGF2 with concurrent intratracheal injection of PPE. To explore the late intervention effect, CBD-FGF2 was intratracheally aerosolized after PPE administration, and lungs were collected after CBD-FGF2 treatment for subsequent analysis., Result: In response to PPE, mice had significantly increased alveolar diameter, collagen deposition and expression of inflammatory factors and decreased lung function indices and expression of alveolar epithelium markers. Our results indicate that CBD-FGF2 administration was able to prevent and repair elastase-induced lung injury partly through the suppression of the inflammatory response and recovery of the alveolar epithelium. The early use of CBD-FGF2 for the prevention of PPE-induced emphysema showed better results than late therapeutic administration against established emphysema., Conclusion: These data provide insight regarding the prospective role of a drug-based option (CBD-FGF2) for preventing and curing emphysema., Competing Interests: Conflict of interest statement The authors declare that there are no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

To evaluate the chest computed tomography (CT) findings of patients with Corona Virus Disease 2019 (COVID-19) on admission to hospital. And then correlate CT pulmonary infiltrates involvement with the findings of emphysema. We analyzed the different infiltrates of COVID-19 pneumonia using emphysema as the grade of pneumonia. We applied open-source assisted software (3D Slicer) to model the lungs and lesions of 66 patients with COVID-19, which were retrospectively included. we divided the 66 COVID-19 patients into the following two groups: (A) 12 patients with less than 10% emphysema in the low-attenuation area less than -950 Hounsfield units (%LAA-950), (B) 54 patients with greater than or equal to 10% emphysema in %LAA-950. Imaging findings were assessed retrospectively by two authors and then pulmonary infiltrates and emphysema volumes were measured on CT using 3D Slicer software. Differences between pulmonary infiltrates, emphysema, Collapsed, affected of patients with CT findings were assessed by Kruskal-Wallis and Wilcoxon test, respectively. Statistical significance was set at p < 0.05. The left lung (A) affected left lung 20.00/affected right lung 18.50, (B) affected left lung 13.00/affected right lung 11.50 was most frequently involved region in COVID-19. In addition, collapsed left lung, (A) collapsed left lung 4.95/collapsed right lung 4.65, (B) collapsed left lung 3.65/collapsed right lung 3.15 was also more severe than the right one. There were significant differences between the Group A and Group B in terms of the percentage of CT involvement in each lung region (p < 0.05), except for the inflated affected total lung (p = 0.152). The median percentage of collapsed left lung in the Group A was 20.00 (14.00-30.00), right lung was 18.50 (13.00-30.25) and the total was 19.00 (13.00-30.00), while the median percentage of collapsed left lung in the Group B was 13.00 (10.00-14.75), right lung was 11.50 (10.00-15.00) and the total was 12.50 (10.00-15.00). The percentage of affected left lung is an independent predictor of emphysema in COVID-19 patients. We need to focus on the left lung of the patient as it is more affected. The people with lower levels of emphysema may have more collapsed segments. The more collapsed segments may lead to more serious clinical feature., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

The pathogenesis of chronic obstructive pulmonary disease (COPD), a prevalent disease primarily caused by cigarette smoke exposure, is incompletely elucidated. Studies in humans and mice have suggested that hypoxia-inducible factor-1α (HIF-1α) may play a role. Reduced lung levels of HIF-1α are associated with decreased vascular density, whereas increased leukocyte HIF-1α may be responsible for increased inflammation. To elucidate the specific role of leukocyte HIF-1α in COPD, we exposed transgenic mice with conditional deletion or overexpression of HIF-1α in leukocytes to cigarette smoke for 7 mo. Outcomes included pulmonary physiology, aerated lung volumes via microcomputed tomography, lung morphometry and histology, and cardiopulmonary hemodynamics. On aggregate, cigarette smoke increased the aerated lung volume, quasi-static lung compliance, inspiratory capacity of all strains while reducing the total alveolar septal volume. Independent of smoke exposure, mice with leukocyte-specific HIF-1α overexpression had increased quasi-static compliance, inspiratory capacity, and alveolar septal volume compared with mice with leukocyte-specific HIF-1α deletion. However, the overall development of cigarette smoke-induced lung disease did not vary relative to control mice for either of the conditional strains. This suggests that the development of murine cigarette smoke-induced airspace disease occurs independently of leukocyte HIF-1α signaling.

Objectives: Both sarcopenia and lung emphysema are prognostic factors in lung cancer and can be easily assessed using the psoas muscle index and Goddard score, respectively. We investigated the clinical significance of the classification based on psoas muscle index and Goddard score in non-small cell lung cancer., Methods: A total of 303 consecutive patients who underwent anatomical resection for non-small cell lung cancer were retrospectively analyzed. The psoas muscle at the level of the third lumbar vertebrae and Goddard score were measured on preoperative computed tomography. The psoas muscle was adjusted by height as the psoas muscle index (cm2/m2). We divided patients into three groups: low-, middle- and high-risk, using cut-off values of psoas muscle index < 6.36 cm2/m2 for males and 3.92 cm2/m2 for females and Goddard score higher than 7. The predictors of postoperative complications and prognosis were examined., Results: High-, middle- and low-risk were present in 30 (10%), 164 (54%) and 109 (36%) patients, respectively. High risk was significantly associated with male sex, low pulmonary function, more comorbidities and increased postoperative complications. High-risk patients showed poorer overall survival than middle- and low-risk patients (P < 0.001). Multivariable analysis revealed that high risk was an independent risk factor for postoperative complications and unfavorable prognostic factors (P = 0.011, P = 0.014, respectively)., Conclusions: Classification based on psoas muscle index and Goddard score is significantly associated with short- and long-term outcomes in patients with lung cancer. This method can be easily assessed for patients and may help select patients for nutritional support and rehabilitation before surgery., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Basic fibroblast growth factor (bFGF) induces regeneration and neovascularization of the lungs. We conducted this study to demonstrate the regeneration of emphysematous lungs achieved by gelatin sheets that slowly release bFGF into the visceral pleura in a canine model., Methods: Porcine pancreatic elastase was used to induce bilateral lower lobe pulmonary emphysema in dogs. Slow-release bFGF gelatin sheets were attached to the visceral pleura of the left lower lobe via thoracotomy. The subjects were divided into two groups: one treated with gelatin sheets containing slow-release bFGF (bFGF + group, n = 5), and the other, treated with only gelatin sheets (bFGF - group, n = 5). The subjects were euthanized after 28 days and histologic lung assessment was performed. The results were evaluated in terms of the mean linear intercept (MLI) and microvessel count., Results: The MLI was significantly shorter in the bFGF + group than in the bFGF - group; (110.0 ± 24.38 vs. 208.9 ± 33.08 μm; P = 0.0006). The microvessel count was not significantly different between the bFGF + and bFGF - groups (12.20 ± 3.007 vs. 5.35 ± 2.3425; P = 0.075); however, it was significantly higher in the bFGF-attached lungs than in the emphysema group (12.20 ± 3.007 vs. 4.57 ± 0.8896; P = 0.012)., Conclusions: Attaching gelatin sheets with slow-release bFGF to the visceral pleura induced lung regeneration and vascularization in a canine pulmonary emphysema model., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Idiopathic lobar emphysema (ILE) and bronchopulmonary sequestration (BPS) are two of the well-characterized pulmonary malformations. Case report: An antenatally detected case of a left bronchopulmonary malformation (BPM) was clinicoradiologically diagnosed to be a left upper lobar emphysema with isolated dextrocardia in the neonatal period. Besides the emphysematous left upper lobe, an accessory lobe akin to an extra lobar BPS was an operative surprise. Histopathological examination of both excised lobes led to a revised diagnosis of a 'hybrid' malformation comprising lobar emphysema and extra lobar BPS. The postoperative recovery was uneventful. Discussion/conclusion: The observations suggest that BPS and ILE may be interim entities in a continuum of abnormal embryogenesis. Such a hybrid malformation has not been hitherto reported.

Cystic lung diseases (CLDs) are a heterogeneous group of pathophysiological entities comprising gas-filled lesions with imperceptible walls, which can occur throughout lung parenchyma. CLDs can arise from different mechanisms and may often have an unpredictable progression. As CLDs are infrequent and may be associated to many different processes, they pose a diagnostic challenge to the radiologist and referring physician. CLDs require a comprehensive diagnostic approach. An essential tool in the evaluation of CLDs is high-resolution computed tomography (HRCT). The first step is in distinction from true cysts, from other cysts mimicking entities, as emphysema, honeycombing, pneumatocoele, cavitate nodules, or bronchiectasis. Thereafter the identification of number, distribution, wall size, and other systemic manifestations provides an accurate characterisation of CLD, often avoiding further evaluation with lung biopsy. Features of pulmonary lucencies, classification of CLDs based on pathophysiological mechanisms, and radiological criteria, the less common aetiologies, and a multidisciplinary approach in pulmonary cysts are reported. Finally, a systematic diagnostic algorithm to guide radiologists in the evaluation of CLDs is discussed., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)