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The aim of this study was to evaluate the effect of ylang-ylang (Cananga odorata) essential oil (YEO) on models of experimental arthritis, persistent inflammation, and nociception in mice. YEO treatment at doses of 100 and 200 mg/kg reduced the infiltration of leukocytes into the joint cavities of mice submitted to zymosan-induced arthritis 6 h and 7 days after arthritis induction. At these doses, YEO treatment reduced the formation of joint edema 4 and 6 h after arthritis induction, and at a dose of 200 mg/kg, YEO treatment reduced mechanical hyperalgesia 3 and 4 h after arthritis induction. At the dose of 200 mg/kg, YEO treatment reduced interleukin-6 (IL-6) levels and cartilage destruction in the zymosan-induced arthritis model, and reduced edema formation and mechanical hyperalgesia in the model of persistent inflammation (21 days) induced by complete Freund’s adjuvant (CFA) in mice. YEO treatment at a dose of 200 mg/kg reduced the nociceptive response in experimental models of nociception induced by acetic acid and formalin. The YEO treatment reduced inflammatory parameters in the experimental arthritis model, and presented antiarthritic, anti-hyperalgesic, antinociceptive, and anti-inflammatory properties.

Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has been proposed as an endotype of chronic critical illness (CCI). The aim of this systematic review is to synthesise the available evidence of risk factors, biomarkers, and biological mechanisms underlying PICS. MEDLINE, CENTRAL, and EMBASE were searched on June 2, 2023. Our population of interest was adult intensive care unit survivors. The exposure group was patients with PICS and the comparator group was patients with no PICS, CCI, or rapid recovery. Mean differences were pooled for each biomarker using a random effects DerSimonian–Laird method. Risk of bias assessment was done using the Newcastle–Ottawa Scale. Six papers were included. Five were single-centre retrospective cohort studies, and one was a prospective cohort study, with sample sizes ranging from 22 to 391 patients. Two studies showed an increased incidence of PICS with age, and two studies showed an association between PICS and Charlson Comorbidity Index scores. PICS was associated with requiring mechanical ventilation in four studies. Meta-analysis showed a 34.4 mg L−1 higher C-reactive protein (95% confidence interval [CI] 12.7–56.2 mg L−1; P <0.01), a 4.4 g L−1 lower albumin (95% CI 0.5–8.3 g L−1; P <0.01), and a 0.36×109 L−1 lower lymphocyte count (95% CI 0.25–0.47×109 L−1; P =0.01) in the PICS compared with the non-PICS group. There are a large variety of other potential biomarkers but limited validation studies. The overall quality of evidence is limited, and these results should be interpreted accordingly. While older patients and those with co-morbidities could be at greater risk for PICS, acquired risk factors, such as injury severity, are potentially more predictive of PICS than intrinsic patient characteristics. There are many potential biomarkers for PICS, but limited validation studies have been conducted. Persistent myeloid-derived suppressor cell expansion, the continual release of danger-associated molecular patterns and pathogen-associated molecular patterns propagating inflammation, and bioenergetic failure are all mechanisms underlying PICS that could offer potential for novel biomarkers and therapeutic interventions. International Prospective Register of Systematic Reviews (PROSPERO; CRD42023427749). [ABSTRACT FROM AUTHOR]

Enhanced critical care delivery has led to improved survival rates in critically ill patients, yet sepsis remains a leading cause of multiorgan failure with variable recovery outcomes. Chronic critical illness, characterised by prolonged ICU stays and persistent end-organ dysfunction, presents a significant challenge in patient management, often requiring multifaceted interventions. Recent research, highlighted in a comprehensive review in the British Journal of Anaesthesia , focuses on addressing the pathophysiological drivers of chronic critical illness, such as persistent inflammation, immunosuppression, and catabolism, through targeted therapeutic strategies including immunomodulation, muscle wasting prevention, nutritional support, and microbiome modulation. Although promising avenues exist, challenges remain in patient heterogeneity, treatment timing, and the need for multimodal approaches. [ABSTRACT FROM AUTHOR]

Early enteral nutrition (EEN) potentially improves immune-related outcomes via the maintenance of intestinal immunity; however, the effects of EEN on clinical outcomes, including infectious complications, are controversial. Therefore, we herein investigated whether EEN affected persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which represents the immunocompromised state after critical illness. This retrospective cohort study utilized the administrative claims database of inpatients and laboratory findings. Patients admitted to and treated in the intensive care unit (ICU) for more than 3 consecutive days were included. The primary outcome, a composite of PICS or mortality on day 14 after admission, was compared between the EEN group, which received enteral nutrition (EN) on the first 3 days (day 0, 1, or 2), and the late enteral nutrition (LEN) group, which did not receive EN on the first 3 days, but then received EN on days 3 through 7, using a propensity score-matched analysis. Secondary outcomes included the composite outcome on day 28, in-hospital mortality, the Barthel index, and laboratory data. Patients who met at least two of the following conditions were diagnosed with PICS: CRP >2.0 mg/dL, albumin <3.0 g/dL, and a lymphocyte count <800/μL. A total of 7530 matched pairs were generated after propensity score matching. The primary outcome was significantly lower in the EEN group (risk difference −3.0%, 95% confidence interval (CI) −4.5 to −1.4%), whereas mortality did not significantly differ. The 28-day composite outcome was similar in the 2 groups (risk difference −1.5%, 95% CI -2.8% to −0.2%, no significant difference in mortality). There was no significant difference in in-hospital mortality between the EEN and LEN groups; however, the Barthel index at discharge was higher in the EEN group (the medians, 50 vs 45, P = 0.001). Laboratory data showed lower Albumin and CRP on day 14 in the EEN group, but no other significant differences. In patients admitted to the ICU, EEN was associated with a lower incidence of PICS on days 14 and 28, but was not associated with mortality. This positive association was not observed in sepsis, cardiac diseases, or gastrointestinal diseases. [ABSTRACT FROM AUTHOR]

Polyacrylic acid (PAA), an organic chemical, has been used as an intermediate in the manufacture of pharmaceuticals and cosmetics. It has been suggested recently that PAA has a high pulmonary inflammatory and fibrotic potential. Although endoplasmic reticulum stress is induced by various external and intracellular stimuli, there have been no reports examining the relationship between PAA-induced lung injury and endoplasmic reticulum stress. F344 rats were intratracheally instilled with dispersed PAA (molecular weight: 269,000) at low (0.5 mg/mL) and high (2.5 mg/mL) doses, and they were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months after exposure. PAA caused extensive inflammation and fibrotic changes in the lungs' histopathology over a month following instillation. Compared to the control group, the mRNA levels of endoplasmic reticulum stress markers Bip and Chop in BALF were significantly increased in the exposure group. In fluorescent immunostaining, both Bip and Chop exhibited co-localization with macrophages. Intratracheal instillation of PAA induced neutrophil inflammation and fibrosis in the rat lung, suggesting that PAA with molecular weight 269,000 may lead to pulmonary disorder. Furthermore, the presence of endoplasmic reticulum stress in macrophages was suggested to be involved in PAA-induced lung injury. [ABSTRACT FROM AUTHOR]

Background: Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is known as a prolonged immunodeficiency that occurs after severe infection. Few studies have demonstrated a direct relationship between PIICS and physical dysfunction in post-intensive care syndrome (PICS). We herein investigated how each component of PICS was affected by the diagnosis of PIICS during hospitalization and examined the relationship between PIICS and PICS using PICS assessments performed at the Hitachi General Hospital PICS Clinic. Methods: The 273 patients who visited the PICS clinic at one month after discharge from the ICU at Hitachi General Hospital were included in the study. We used the diagnostic criteria for PIICS described in previous studies. At least two of the following blood test values on day 14 of hospitalization had to be met for a diagnosis of PIICS: C-reactive protein (CRP) > 2.0 mg/dL, albumin (Alb) < 3.0 g/dL, and lymphocytes (Lym) < 800/μL. Blood test values closest to day 14 out of 11–17 days of hospitalization were used. The primary outcome was a Barthel Index (BI) < 90, while secondary outcomes were the results of various PICS assessments, including mental and cognitive impairments, performed at the PICS clinic. We supplemented missing data with multiple imputations by chained equations. We performed a nominal logistic regression analysis with age, sex, BMI, SOFA, and the presence of PIICS as variables for BI < 90. Results: Forty-three out of two hundred seventy-three PICS outpatients met the diagnostic criteria for PIICS during hospitalization. In comparisons with non-PIICS patients, significantly higher severity scores for APACHE II and SOFA and a longer hospital stay were observed in PIICS patients, suggesting a higher clinical severity. The primary outcome, BI, was lower in the PIICS group (97.5 (58.5, 100) vs. 100 (95, 100), p = 0.008), as were the secondary outcomes (FSS-ICU: 35 (31, 35) vs. 35 (35, 35), MRC score: 55 (50.25, 58) vs. 58 (53, 60), grip strength: 16.45 (9.2, 25.47) vs. 20.4 (15.3, 27.7)). No significant differences were noted in mental or cognitive function assessments, such as HADS, IES-R, and SMQ. A multivariable analysis supplemented with missing data revealed that PIICS (odds ratio: 1.23 (1.08–1.40 p = 0.001) and age (odds ratio: 1.007 (1.004–1.01), p < 0.001) correlated with BI < 90, independent of clinical severity such as sequential organ failure assessment (SOFA). Similar results were obtained in the sensitivity analysis excluding missing data. Conclusions: The present study revealed a strong relationship between PIICS and post-discharge PICS physical dysfunction in patients requiring intensive care. [ABSTRACT FROM AUTHOR]

Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) is a serious condition after critical care. We examined the efficacy of antithrombin, which may attenuate coagulopathy with the control of inflammation, for PICS among patients with sepsis-induced disseminated intravascular coagulation (DIC). The present study used the inpatient claims database with laboratory findings to identify patients admitted to intensive care units and diagnosed with sepsis and DIC. A composite of the incidence of PICS on day 14 or 14-day mortality as the primary outcome was compared between the antithrombin and control groups using a propensity-score-matched analysis. Secondary outcomes were the incidence of PICS on day 28, 28-day mortality, and in-hospital mortality. A total of 324 well-balanced matched pairs were generated from 1622 patients. The primary outcome did not differ between the antithrombin and control groups (63.9% vs. 68.2%, respectively, p = 0.245). However, the incidences of 28-day and in-hospital mortality were significantly lower in the antithrombin group (16.0% vs. 23.5% and 24.4% vs. 35.8%, respectively). Similar results were obtained in a sensitivity analysis using overlap weighting. Antithrombin did not reduce the occurrence of PICS on day 14 in patients with sepsis-induced DIC; however, it was associated with a better mid-term (day 28) prognosis. [ABSTRACT FROM AUTHOR]

BackgroundPersistent Inflammation, Immunosuppression, and Catabolism Syndrome (PIICS) is a significant contributor to adverse long-term outcomes in severe trauma patients.ObjectiveThe objective of this study was to establish and validate a PIICS predictive model in severe trauma patients, providing a practical tool for early clinical prediction.Patients and methodsAdult severe trauma patients with an Injury Severity Score (ISS) of ≥16, admitted between October 2020 and December 2022, were randomly divided into a training set and a validation set in a 7:3 ratio. Patients were classified into PIICS and non-PIICS groups based on diagnostic criteria. LASSO regression was used to select appropriate variables for constructing the prognostic model. A logistic regression model was developed and presented in the form of a nomogram. The performance of the model was evaluated using calibration and ROC curves.ResultsA total of 215 patients were included, consisting of 155 males (72.1%) and 60 females (27.9%), with a median age of 51 years (range: 38–59). NRS2002, ISS, APACHE II, and SOFA scores were selected using LASSO regression to construct the prognostic model. The AUC of the ROC analysis for the predictive model in the validation set was 0.84 (95% CI 0.72–0.95). The Hosmer-Lemeshow test in the validation set yielded a χ2 value of 14.74, with a value of p of 0.098.ConclusionAn accurate and easily implementable PIICS risk prediction model was established. It can enhance risk stratification during hospitalization for severe trauma patients, providing a novel approach for prognostic prediction.

Purpose: Multiple organ failure (MOF) is a disease group that necessitates intensive care monitoring and carries a significant mortality rate. If these individuals are not dead as a result of early MOF, they will either quickly restore immunological balance or their immunological dysfunction may persist, resulting in chronic critical illness (CCI). Some of these patients have CCI, which is characterized by chronic inflammation, immunosuppression, and the syndrome of catabolism (PICS). With this study, we aimed to evaluate PICS cases in our intensive care unit, their effects on mortality, and their biomarkers. Materials and Methods: This is a retrospective, observational study involving 190 patients diagnosed with acute respiratory distress syndrome (ARDS) due to SARSCoV-2 and followed up in the ICU. Patients' laboratory data and body mass index (BMI) were compared between the first and twenty-first days of ICU admission. In addition, the patients were evaluated according to PICS utilizing the number of days they spent in the ICU, CRP, albumin, prealbumin, lymphocytes, and BMI data. Results: The laboratory values of the patients on the 21st day were as follows, and the results obtained were statistically significant when compared with the values on the 1st day. Albumin 2.56±0.57 g/L, prealbumin 9±15 g/L, d-dimer 4.41±4.70 (interquartile range (IQR): 2.53-4.76) µgFEU/mL, fibrinogen 497±189,35 mg/dl, hemoglobin 10.15±1.82 g/dL, leukocytes 13.94±8.12 (IQR: 12.34-7.69) 109/L, immature granulocyte 1.16±2.13 (IQR: 0.46-1)109/L and BMI of 26.92±3.27 (IQR: 26.7-4.8). Again in these patients, lymphocyte values were 0.92±0.80 (IQR: 0.71-0.74)109/L, CRP was 101.42±99,96 mg/L, and platelet values were 214.24±128.08 109/L. Conclusion: PICS is a significant condition affecting mortality and morbidity in critical care patients. In this group of patients, immature granulocytes may also serve as a useful biomarker. Due to the lack of studies regarding PICS, we are in the premature phase of understanding the pathogenesis and management of PICS and therefore need more comprehensive research regarding the topic. [ABSTRACT FROM AUTHOR]

Abstract Background As carcinogenic risk factors, environmental factors can be classified into physical, biological, and chemical factors. Subperiosteal implants (SIs) are associated with complications, such as framework exposure, infection, and fistula formation. A current hypothesis suggests that chronic mechanical irritation could be a co-factor in carcinogenesis, while peri-implantitis might be an initiating or promoting agent in the development of oral mucosal cancer. Herein, we report a case of squamous cell carcinoma (SCC) around a maxillary SI associated with chronic mechanical irritation and peri-implantitis as physical and biological factors, respectively. Case presentation A 74-year-old male patient presented with severe mobility of the SI and an undermined ulcer with induration, accompanied by a palatal fistula and the exposure of the metal framework. The SI had been placed on the maxilla for the occlusal reconstruction of the molar area 20 years ago. An incisional biopsy of the ulcer revealed SCC (cT4aN2cM0). Neoadjuvant chemotherapy was initiated, followed by bilateral neck dissection and partial resection of the maxilla with SI removal. Energy-dispersive X-ray analysis suggested that the SI was fabricated using pure titanium, and titanium was absent in the specimen. Scanning electron microscopy of the SI in contact with the SCC showed a few microcracks, suggesting pitting corrosion. Discussion Chronic mechanical irritation due to the mobility of an improperly designed SI can be a physical factor, and prolonged peri-implantitis without regular maintenance can be a biological factor in carcinogenesis. Improperly designed main struts and a large masticatory force in the molar area resulted in deterioration of the retention and mobility of the SI. The screw and framework frequently moved on mastication and came in direct contact with the ulcer as chronic mechanical irritation. Bacterial invasion into the subperiosteal space expanded by the mobility of the metal framework led to peri-implantitis. The influence of chemical factors was considered relatively small in this case since the patient had no history of smoking or drinking, and titanium was absent in the specimen. Therefore, it is conceivable that SCC can arise owing to persistent inflammation caused by chronic mechanical irritation and peri-implantitis as physical and biological factors, respectively.

Purpose of Review: The balance between inflammation and its resolution plays an important and increasingly appreciated role in heart failure (HF) pathogenesis. In humans, different chronic inflammatory conditions and immune-inflammatory responses to infection can lead to diverse HF manifestations. Reviewing the phenotypic and mechanistic diversity of these HF presentations offers useful clinical and scientific insights. Recent Findings: HF risk is increased in patients with chronic inflammatory and autoimmune disorders and relates to disease severity. Inflammatory condition–specific HF manifestations exist and underlying pathophysiologic causes may differ across conditions. Summary: Although inflammatory disease–specific presentations of HF differ, chronic excess in inflammation and auto-inflammation relative to resolution of this inflammation is a common underlying contributor to HF. Further studies are needed to phenotypically refine inflammatory condition–specific HF pathophysiologies and prognoses, as well as potential targets for intervention. [ABSTRACT FROM AUTHOR]

Objectives: Persistent inflammation is an insidious feature of familial Mediterranean fever (FMF) that may cause chronic complications. This study aimed to investigate the predictors of persistent inflammation in children with FMF. Methods: The medical charts of 1077 paediatric FMF patients were retrospectively collected. The patients were divided into two groups: with and without subclinical inflammation. Results: A total of 133 (12%) patients had persistent inflammation. M694V homozygosity, colchicine resistance, positive family history for FMF, erysipelas-like erythema, leg pain, arthritis, chest pain, inflammatory comorbidities, early disease onset, high PRAS score, and long attack duration were established as independent predictors of persistent inflammation (P < .001, P < .001, P < .001, P < .001, P =0.006, P < .001, P < .001, P =.014, P < .001, P < .001, and P < .001, respectively). However, gender, abdominal pain, fever, and attack frequency were not found to be independent risk factors for predicting persistent inflammation (P =.412, P =.531, P =.451, and P =.693, respectively). Conclusions: M694V homozygosity, colchicine resistance, positive family history, erysipelas-like erythema, leg pain, arthritis, chest pain, inflammatory comorbidities, early disease onset, high activity score, and long attack duration may be predictors of persistent inflammation in FMF. These predictors may help clinicians suspect the occurrence of subclinical inflammation and should aid in better disease management in FMF. [ABSTRACT FROM AUTHOR]

Objective: To characterize endothelial function, inflammation, and immunosuppression in surgical patients with distinct clinical trajectories of AKI and to determine the impact of persistent kidney injury and renal non-recovery on clinical outcomes, resource utilization, and long-term disability and survival. Summary of Background Data: AKI is associated with increased healthcare costs and mortality. Trajectories that account for duration and recovery of AKI have not been described for sepsis patients, who are uniquely vulnerable to renal dysfunction. Methods: This prospective observational study included 239 sepsis patients admitted and enrolled between January 2015 and July 2017. Kidney Disease: Improving Global Outcomes (KDIGO) and Acute Disease Quality Initiative (ADQI) criteria were used to classify subjects as having no AK I, rapidly reversed AKI, persistent AKI with renal recovery, or persistent AK I without renal recovery. Serial biomarker profiles, clinical outcomes, resource utilization, and long-term physical performance status and survival were compared among AKI trajectories. Results: Sixty-two percent of the study population developed AKI. Only one-third of AKI episodes rapidly reversed within 48 hours; the remaining had persistent AKI , among which 57% did not have renal recovery by discharge. One-year survival and proportion of subjects fully active 1 year after sepsis was lowest among patients with persistent AKI compared with other groups. Long-term mortality hazard rates were 5-fold higher for persistent AKI without renal recovery compared with no AKI. Conclusions: Among critically ill surgical sepsis patients, persistent AKI and the absence of renal recovery are associated with distinct early and sustained immunologic and endothelial biomarker signatures and decreased long-term physical function and survival. [ABSTRACT FROM AUTHOR]

Monocytes/macrophages play a prominent role in cutaneous wound healing. Persistent inflammation in diabetic wounds is associated with the inability of monocytic cells to switch from a phagocytic M1 (classically activated) to an anti-inflammatory, pro-regenerative M2 (alternatively activated) phenotype and as consequence, the proliferative phase of healing does not commence. A targeted cell therapy approach could potentially restore the pathological wound microenvironment through paracrine signalling to enable healing. This study investigated whether in vitro pre-treatment of monocytic (J774.1 A) cells - using a combination of endotoxin-induced immune tolerance (Pam3CSK4) and M2 polarization (IL-4) - could make these cells impervious to the pathological wound microenvironment and enhance the release of anti-inflammatory cytokines/growth factors. The effect of Pam3CSK4-induced tolerance and IL-4-associated polarization was assessed independently and in combination, on the expression of intracellular (flow cytometry) and secreted (ELISA) cytokines (TNF-ɑ, IL-6, IL-10, TGF-β) with and without re-stimulation to define the optimal pre-treatment conditions. Successive pre-treatment approach consisting of endotoxin tolerance followed by IL-4 priming, dampened TNF-ɑ release and induced intracellular TGF-β production upon re-stimulation. To mimic a chronic wound microenvironment, the J774A.1 monocytes were differentiated into macrophages using GM-CSF prior to pre-treatment (optimal condition) and subsequently exposed to diabetic wound fluid. The data demonstrated that in the presence of wound fluid, the successive pre-treatment, promoted M2 polarization (CD206) of monocytic cells and significantly dampened the intracellular production of both pro-inflammatory (TNF-ɑ, IL-6) and anti-inflammatory (IL-10, TGF-β) cytokines. • Pre-treatment of monocytic cells can modulate paracrine factors. • IL-4 induced M2 polarization of monocytic cells triggers TNFɑ release. • Endotoxin-induced tolerance followed by M2 polarization blunted TNFɑ release. • Endotoxin-induced tolerance followed by M2 polarization promoted CD206 expression. • Tolerized/M2 macrophages had overall blunted cytokine response to wound fluid. [ABSTRACT FROM AUTHOR]

Owing to the development of intensive care units, many patients survive their initial insults but progress to chronic critical illness (CCI). Patients with CCI are characterized by prolonged hospitalization, poor outcomes, and significant long-term mortality. Some of these patients get into a state of persistent low-grade inflammation, suppressed immunity, and ongoing catabolism, which was defined as persistent inflammation, immunosuppression, and catabolism syndrome (PICS) in 2012. Over the past few years, some progress has been made in the treatment of PICS. However, most of the existing studies are about the role of persistent inflammation and suppressed immunity in PICS. As one of the hallmarks of PICS, hypercatabolism has received little research attention. In this review, we explore the potential pathophysiological changes and molecular mechanisms of hypercatabolism and its role in PICS. In addition, we summarize current therapies for improving the hypercatabolic status and recommendations for patients with PICS.

Background: As carcinogenic risk factors, environmental factors can be classified into physical, biological, and chemical factors. Subperiosteal implants (SIs) are associated with complications, such as framework exposure, infection, and fistula formation. A current hypothesis suggests that chronic mechanical irritation could be a co-factor in carcinogenesis, while peri-implantitis might be an initiating or promoting agent in the development of oral mucosal cancer. Herein, we report a case of squamous cell carcinoma (SCC) around a maxillary SI associated with chronic mechanical irritation and peri-implantitis as physical and biological factors, respectively. Case presentation: A 74-year-old male patient presented with severe mobility of the SI and an undermined ulcer with induration, accompanied by a palatal fistula and the exposure of the metal framework. The SI had been placed on the maxilla for the occlusal reconstruction of the molar area 20 years ago. An incisional biopsy of the ulcer revealed SCC (cT4aN2cM0). Neoadjuvant chemotherapy was initiated, followed by bilateral neck dissection and partial resection of the maxilla with SI removal. Energy-dispersive X-ray analysis suggested that the SI was fabricated using pure titanium, and titanium was absent in the specimen. Scanning electron microscopy of the SI in contact with the SCC showed a few microcracks, suggesting pitting corrosion. Discussion: Chronic mechanical irritation due to the mobility of an improperly designed SI can be a physical factor, and prolonged peri-implantitis without regular maintenance can be a biological factor in carcinogenesis. Improperly designed main struts and a large masticatory force in the molar area resulted in deterioration of the retention and mobility of the SI. The screw and framework frequently moved on mastication and came in direct contact with the ulcer as chronic mechanical irritation. Bacterial invasion into the subperiosteal space expanded by the mobility of the metal framework led to peri-implantitis. The influence of chemical factors was considered relatively small in this case since the patient had no history of smoking or drinking, and titanium was absent in the specimen. Therefore, it is conceivable that SCC can arise owing to persistent inflammation caused by chronic mechanical irritation and peri-implantitis as physical and biological factors, respectively. [ABSTRACT FROM AUTHOR]

Giovanna De Cunto, Eleonora Cavarra, Barbara Bartalesi, Monica Lucattelli, Giuseppe Lungarella Department of Molecular and Developmental Medicine, University of Siena, Siena, ItalyCorrespondence: Giuseppe Lungarella Email lungarella.giuseppe@gmail.comAbstract: Chronic obstructive pulmonary disease (COPD) is mainly associated with smoking habit. Inflammation is the major initiating process whereby neutrophils and monocytes are attracted into the lung microenvironment by external stimuli present in tobacco leaves and in cigarette smoke, which promote chemotaxis, adhesion, phagocytosis, release of superoxide anions and enzyme granule contents. A minority of smokers develops COPD and different molecular factors, which contribute to the onset of the disease, have been put forward. After many years of research, the pathogenesis of COPD is still an object of debate. In vivo models of cigarette smoke-induced COPD may help to unravel cellular and molecular mechanisms underlying the pathogenesis of COPD. The mouse represents the most favored animal choice with regard to the study of immune mechanisms due to its genetic and physiological similarities to humans, the availability of a large variability of inbred strains, the presence in the species of several genetic disorders analogous to those in man, and finally on the possibility to create models “made-to-measure” by genetic manipulation. The review outlines the different response of mouse strains to cigarette smoke used in COPD studies while retaining a strong focus on their relatability to human patients. These studies reveal the importance of innate immunity and cell surface receptors in the pathogenesis of pulmonary injury induced by cigarette smoking. They further advance the way in which we use wild type or genetically manipulated strains to improve our overall understanding of a multifaceted disease such as COPD. The structural and functional features, which have been found in the different strains of mice after chronic exposure to cigarette smoke, can be used in preclinical studies to develop effective new therapeutic agents for the different phenotypes in human COPD.Keywords: cigarette smoking, emphysema, airway remodelling, vascular remodelling, smoking cessation, persistent inflammation

Background: Early enteral nutrition (EN) is recommended for patients with critical illness to maintain intestinal immunity. However, the optimal timing of the commencement of EN remains unclear, particularly after cardiovascular surgery., Objectives: We herein focused on Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) as a predisposing immunodeficiency and investigated its association with very early EN (VEEN) (<24 h) in patients who underwent cardiovascular surgery., Methods: In this retrospective study, we used an administrative claims database with laboratory examinations between 2008 and 2021 to identify adult patients admitted to the intensive care unit after cardiovascular surgery. Patients who received EN the day after surgery were assigned to the EN <24 h group, whereas those who received EN on day 2 or day 3 were assigned to the control group. The primary outcome was a composite of the incidence of PICS and mortality on day 14 after surgery. We defined PICS as patients who were hospitalized for >14 day and meeting ≥2 of the following conditions: a lymphocyte count <800/μL, albumin <3.0 g/dL, and C-reactive protein >2.0 mg/dL. We compared the 2 groups using propensity score analysis., Results: A propensity score matching generated 2082 pairs. The primary outcome was significantly lower in the EN <24 h group than in the control group on days 14 {risk difference [95% confidence interval (CI)]: -3.1% [-5.9%, -0.3%]} and 28 (risk difference [95% CI]: -2.1% [-3.7%, -0.4%]). Mortality did not significantly differ between the 2 groups. The length of hospital stay was significantly shorter in the EN <24 h group: the difference (95% CI) was -2.2 (-3.7, -0.7) d., Conclusions: Among patients who underwent cardiovascular surgery, VEEN provided on the day after surgery was associated with a lower incidence of PICS and a shorter length of hospital stay than EN provided 2 day or 3 day after surgery., Competing Interests: Conflict of interest The authors report no conflicts of interest., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Objectives: We conducted inhalation and intratracheal instillation studies in order to examine the effects of tungsten trioxide (WO3) nanoparticles on the lung, and evaluated whether or not the nanoparticles would cause persistent lung inflammation. Methods: In the inhalation study, male 10‐week‐old Fischer 334 rats were classified into 3 groups. The control, low‐dose, and high‐dose groups inhaled clean air, 2, and 10 mg/m3 WO3 nanoparticles, respectively, for 6 h each day for 4 weeks. The rats were dissected at 3 days, 1 month, and 3 months after the inhalation, and the bronchoalveolar lavage fluid (BALF) and lung tissue were examined. In the intratracheal instillation study, male 12‐week‐old Fischer 334 rats were divided into 3 subgroups. The control, low‐dose, and high‐dose groups were intratracheally instilled 0.4 ml distilled water, 0.2, and 1.0 mg WO3 nanoparticles, respectively, dissolved in 0.4 ml distilled water. The rats were sacrificed at 3 days, 1 week, and 1 month after the intratracheal instillation, and the BALF and lung tissue were analyzed as in the inhalation study. Results: The inhalation and instillation of WO3 nanoparticles caused transient increases in the number and rate of neutrophils, cytokine‐induced neutrophil chemoattractant (CINC)‐1, and CINC‐2 in BALF, but no histopathological changes or upregulation of heme oxygenase (HO)‐1 in the lung tissue. Conclusion: Our results suggest that WO3 nanoparticles have low toxicity to the lung. According to the results of the inhalation study, we also propose that the no observed adverse effect level (NOAEL) of WO3 nanoparticles is 2 mg/m3. [ABSTRACT FROM AUTHOR]

Objective: To analyze serial biomarkers of the persistent inflammation, immunosuppression, and catabolism syndrome (PICS) to gain insight into the pathobiology of chronic critical illness (CCI) after surgical sepsis. Background: Although early deaths after surgical intensive care unit sepsis have decreased and most survivors rapidly recover (RAP), one third develop the adverse clinical trajectory of CCI. However, the underlying pathobiology of its dismal long-term outcomes remains unclear. Methods: PICS biomarkers over 14 days from 124 CCI and 225 RAP sepsis survivors were analyzed to determine associations and prediction models for (1) CCI (≥14 intensive care unit days with organ dysfunction) and (2) dismal 1-year outcomes (Zubrod 4/5 performance scores). Clinical prediction models were created using PIRO variables (predisposition, insult, response, and organ dysfunction). Biomarkers were then added to determine if they strengthened predictions. Results: CCI (vs RAP) and Zubrod 4/5 (vs Zubrod 0–3) cohorts had greater elevations in biomarkers of inflammation (interleukin [IL]-6, IL-8, interferon gamma-induced protein [IP-10], monocyte chemoattractant protein 1), immunosuppression (IL-10, soluble programmed death ligand-1), stress metabolism (C-reactive protein, glucagon-like peptide 1), and angiogenesis (angiopoietin-2, vascular endothelial growth factor, vascular endothelial growth factor receptor-1, stromal cell-derived factor) at most time-points. Clinical models predicted CCI on day 4 (area under the receiver operating characteristics curve [AUC] = 0.89) and 1 year Zubrod 4/5 on day 7 (AUC = 0.80). IL-10 and IP-10 on day 4 minimally improved prediction of CCI (AUC = 0.90). However, IL-10, IL-6, IL-8, monocyte chemoattractant protein 1, IP-10, angiopoietin-2, glucagon-like peptide 1, soluble programmed death ligand-1, and stromal cell-derived factor on day 7 considerably improved the prediction of Zubrod 4/5 status (AUC = 0.88). Conclusions: Persistent elevations of PICS biomarkers in the CCI and Zubrod 4/5 cohorts and their improved prediction of Zubrod 4/5 validate that PICS plays a role in CCI pathobiology. [ABSTRACT FROM AUTHOR]

Objective Persistent inflammation is an insidious and less studied feature of FMF. We investigated clinical determinants of persistent inflammation and its associations with individual damage items. Methods This is a cross-sectional analysis of 917 FMF patients, who fulfilled the Tel Hashomer criteria and had at least 6 months' follow-up. Patients were stratified based on whether they had persistent inflammation. We used logistic regression analysis to investigate independent predictors of persistent inflammation and the associated individual damage items. Results One hundred and forty-two (15%) patients had persistent inflammation. Active FMF (54%) was the most prominent reason for the persistent inflammation. Spondylarthritis (16%), other inflammatory arthritis (8%) and IBD (2%) were other frequent reasons. Male gender, history of exertional leg pain, inflammatory comorbidities, M694V homozygosity, colchicine resistance, lower education levels and musculoskeletal attack dominance were found to be the independent predictors of persistent inflammation. Earlier disease onset led to a tendency towards persistent inflammation. Patients with persistent inflammation were more likely to suffer damage. There is an increased risk of developing proteinuria, amyloidosis and renal insufficiency. Conclusion We identified, for the first time, the predictors of persistent inflammation in adult FMF patients and related individual damage items of the Autoinflammatory Disease Damage Index. Persistent inflammation is insidious and one of the chief causes of damage; therefore, especially patients with these predictors should be followed up more closely. If detected, underlying inflammatory comorbidities should be assessed meticulously as early detection and proper treatment strategies may favourably impact the natural history of the disease. [ABSTRACT FROM AUTHOR]

Polyhexamethyleneguanidine phosphate (PHMG-P) is one of the causative agents of humidifier disinfectant-induced lung injury. Direct exposure of the lungs to PHMG-P causes interstitial pneumonia with fibrosis. Epidemiological studies showed that patients with humidifier disinfectant-associated lung injuries have suffered from restrictive lung function five years after the onset of the lung injuries. We investigated whether lung damage was sustained after repeated exposure to PHMG-P followed by a long-term recovery and evaluated the adverse effects of PHMG-P on mice lungs. Mice were intranasally instilled with 0.3 mg/kg PHMG-P six times at two weeks intervals, followed by a recovery period of 292 days. Histopathological examination of the lungs showed the infiltration of inflammatory cells, the accumulation of extracellular matrix in the lung parenchyma, proteinaceous substances in the alveoli and bronchiolar–alveolar hyperplasia. From RNA-seq, the gene expression levels associated with the inflammatory response, leukocyte chemotaxis and fibrosis were significantly upregulated, whereas genes associated with epithelial/endothelial cells development, angiogenesis and smooth muscle contraction were markedly decreased. These results imply that persistent inflammation and fibrotic changes caused by repeated exposure to PHMG-P led to the downregulation of muscle and vascular development and lung dysfunction. Most importantly, this pathological structural remodeling induced by PHMG-P was not reversed even after long-term recovery.

Signal Transducer and Activator of Transcription 1 (STAT1) is a DNA‐binding signal transducer that regulates transcription of specific genes in response to IFNγ and IFNα/β stimulation. Loss‐of‐function mutations impairing STAT1 activity are known to confer susceptibility to intracellular bacterial and viral diseases. Conversely, the few known activating mutations of STAT1 allow predisposition to chronic mucocutaneous candidiasis disease, and occur in patients with combined immunodeficiency and defective Th1 and Th17 responses. Here, we report on a de novo gain‐of‐function (GoF) STAT1 mutation (c.1398C>G, p.Ser466Arg) identified by exome sequencing in an individual with brain calcification, arthritis, recurrent pericarditis, leukopenia, thrombocytopenia and low C3 levels, a phenotype resembling an interferonopathy. The Ser466Arg change affects a highly conserved residue located in the DNA binding domain of the protein and the amino acid substitution was documented to have an activating role both in vitro and in vivo. Altogether, clinical features and functional studies are compatible with hyperactivation of the Interferon pathways, highlighting a role of STAT1 GoF mutation in clinical phenotypes fitting interferonopathies. [ABSTRACT FROM AUTHOR]

This work aimed to explore whether the persistent inflammation induced by lipopolysaccharide (LPS) ameliorates fat accumulation by promoting adipose browning in vitro and in vivo. LPS over 1 ng/mL reduced lipid accumulation while increasing the expressions of specific genes involved in inflammation, mitochondrial biogenesis, and adipose browning in 3T3-L1 adipocytes. Moreover, LPS in intraperitoneal injection decreased white adipose tissue weight and elevated interscapular brown adipose tissue weight in mice. According to RT-PCR and western blot analysis results, the expressions of genes and proteins related to inflammation, mitochondrial biogenesis, lipolysis, and brown or beige markers in different tissues were elevated after LPS intervention. Cumulatively, LPS-induced persistent inflammation may potentially ameliorate fat accumulation by facilitating adipose browning in 3T3-L1 adipocytes and mice. These results offer new perspectives into the effect of persistent inflammation induced by LPS on regulating fat metabolism, thereby reducing fat accumulation by boosting adipose browning procedure. [Display omitted] • LPS increases brown or beige-specific markers to promote adipose browning. • LPS affects mitochondrial biogenesis to promote thermogenesis and inhibit fat storage. • LPS-induced persistent inflammation promotes fat metabolism in mice. [ABSTRACT FROM AUTHOR]

The reasonability of using nonsteroidal anti-inflammatory drugs (NSAIDs) in osteoarthritis (OA) is due mainly to persistent articular tissue inflammation that contributes to the progression of structural changes in the hyaline cartilage, as well as its leading clinical manifestation – pain syndrome caused by damage to different articular structures. NSAIDs are basic rapid-acting symptom-modifying drugs in the treatment of OA. Meloxicam has high anti-inflammatory and analgesic activities. The effect of meloxicam on hyaline cartilage metabolism permits one to consider it as a potential chondroprotective agent. Short- and long-term investigations have demonstrated its good tolerability, including that in patients with polymorbidity. The use of meloxicam does not increase the risk of cardiac and renal complications. The high therapeutic activity of meloxicam along with the low level of adverse reactions determines the pharmacoeconomic expediency of its use.

Severe acute pancreatitis (SAP) is a severe disease with a high prevalence and a 3-15% mortality worldwide, and premature activation of zymogen for any reason is the initial factor for the onset of SAP. Gallstone disease and heavy alcohol consumption are the two most common etiologies of SAP. Persistent inflammation, immunosuppression and catabolism syndrome (PICS) is a life-threatening illness, and there are no effective treatments. The relapse state of PICS mainly leads to high mortality due to septic shock or severe trauma, both of which are dangerous and challenging conditions for clinicians. Thus, it is important for medical staff to identify patients at high risk of PICS and to master the prevention and treatment of PICS in patients with SAP. The present review aims to increase the understanding of the pathogenesis of PICS, produce evidence for PICS diagnosis and highlight clinical treatment for PICS in patients with SAP. With this information, clinical workers could implement standardized and integrated measures at an early stage of SAP to stop its progression to PICS. [ABSTRACT FROM AUTHOR]

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The rostral ventromedial medulla (RVM) is a relay in the descending pain modulatory system and an important site of endocannabinoid modulation of pain. Endocannabinoids inhibit GABA release in the RVM, but it is not known whether this effect persists in chronic pain states. In the present studies, persistent inflammation induced by complete Freund's adjuvant (CFA) increased GABAergic miniature IPSCs (mIPSCs). Endocannabinoid activation of cannabinoid (CB1) receptors known to inhibit presynaptic GABA release was significantly reduced in theRVMof CFA-treated rats compared with naive rats. The reduction in CFA-treated rats correlated with decreased CB1 receptor protein expression and function in the RVM. Paradoxically, the nonselective CB1/CB2 receptor agonist WIN55212 inhibited GABAergic mIPSCs in both naive and CFA-treated rats. However, WIN55212 inhibition was reversed by the CB1 receptor antagonist rimonabant in naive rats but not in CFA-treated rats. WIN55212-mediated inhibition in CFA-treated rats was blocked by the CB2 receptor-selective antagonist SR144528, indicating that CB2 receptor function in the RVM is increased during persistent inflammation. Consistent with these results, CB2 receptor agonists AM1241 and GW405833 inhibited GABAergic mIPSC frequency only in CFA-treated rats, and the inhibition was reversed with SR144528. When administered alone, SR144528 and another CB2 receptor-selective antagonist AM630 increased mIPSC frequency in the RVM of CFA-treated rats, indicating that CB2 receptors are tonically activated by endocannabinoids. Our data provide evidence that CB2 receptor function emerges in the RVM in persistent inflammation and that selective CB2 receptor agonists may be useful for treatment of persistent inflammatory pain. [ABSTRACT FROM AUTHOR]

A case-cohort analysis of human immunodeficiency virus (HIV)-infected individuals receiving antiretroviral therapy (ART) was performed within a multicountry randomized trial (PEARLS) to assess the prevalence of persistently elevated C-reactive protein (CRP) levels, based on serial measurements of CRP levels, and their association with HIV clinical failure. A persistently elevated CRP level in plasma (defined as ≥ 5 mg/L at both baseline and 24 weeks after ART initiation) was observed in 50 of 205 individuals (24%). A persistently elevated CRP level but not an elevated CRP level only at a single time point was independently associated with increased clinical failure, compared with a persistently low CRP level, despite achievement of virologic suppression. Serial monitoring of CRP levels could identify individuals who are at highest risk of HIV progression and may benefit from future adjunct antiinflammatory therapies. [ABSTRACT FROM AUTHOR]