Search

Interstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILA are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral.

A hallmark of idiopathic pulmonary fibrosis is the excess accumulation of extracellular matrix in the lungs. Degradation of extracellular matrix generates free-circulating protein fragments called neoepitopes. The aim of the INMARK trial was to investigate changes in neoepitopes as predictors of disease progression in patients with idiopathic pulmonary fibrosis and the effect of nintedanib on these biomarkers.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease with a better prognosis, on average, than idiopathic pulmonary fibrosis (IPF). We compare survival time and pulmonary function trajectory in patients with HP and IPF by radiologic phenotype.

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with few effective therapeutic options. Structural remodelling of the extracellular matrix [i.e. collagen cross-linking mediated by the lysyl oxidase (LO) family of enzymes (LOX, LOXL1-4)] might contribute to disease pathogenesis and represent a therapeutic target. This study aimed to further our understanding of the mechanisms by which LO inhibitors might improve lung fibrosis. Lung tissues from IPF and non-IPF subjects were examined for collagen structure (second harmonic generation imaging) and LO gene (microarray analysis) and protein (immunohistochemistry and western blotting) levels. Functional effects (collagen structure and tissue stiffness using atomic force microscopy) of LO inhibitors on collagen remodelling were examined in two models, collagen hydrogels and decellularized human lung matrices. LOXL1/LOXL2 gene expression and protein levels were increased in IPF versus non-IPF. Increased collagen fibril thickness in IPF versus non-IPF lung tissues correlated with increased LOXL1/LOXL2, and decreased LOX, protein expression. β-Aminoproprionitrile (β-APN; pan-LO inhibitor) but not Compound A (LOXL2-specific inhibitor) interfered with transforming growth factor-β-induced collagen remodelling in both models. The β-APN treatment group was tested further, and β-APN was found to interfere with stiffening in the decellularized matrix model. LOXL1 activity might drive collagen remodelling in IPF lungs. The interrelationship between collagen structural remodelling and LOs is disrupted in IPF lungs. Inhibition of LO activity alleviates fibrosis by limiting fibrillar collagen cross-linking, thereby potentially impeding the formation of a pathological microenvironment in IPF.

Surgical lung biopsy (SLB) is invasive and not possible in all patients with undiagnosed interstitial lung disease (ILD). We hypothesized that transbronchial biopsy (TBB) findings combined with clinical and high-resolution CT (HRCT) data leads to a confident diagnosis congruent to SLB and therefore avoids the need for SLB in some patients.

With the recent development of two effective treatments for patients with idiopathic pulmonary fibrosis, an accurate diagnosis is crucial. The traditional approach to diagnosis emphasises the importance of thorough clinical and laboratory evaluations to exclude secondary causes of disease. High-resolution CT is a critical initial diagnostic test and acts as a tool to identify patients who should undergo surgical lung biopsy to secure a definitive histological diagnosis of usual interstitial pneumonia pattern. This diagnostic approach faces several challenges. Many patients with suspected idiopathic pulmonary fibrosis present with atypical high-resolution CT characteristics but are unfit for surgical lung biopsy, therefore preventing a confident diagnosis. The state of the art suggests an iterative, multidisciplinary process that incorporates available clinical, laboratory, imaging, and histological features. Recent research has explored genomic techniques to molecularly phenotype patients with interstitial lung disease. In the future, clinicians will probably use blood-specific or lung-specific molecular markers in combination with other clinical, physiological, and imaging features to enhance diagnostic efforts, refine prognostic recommendations, and influence the initial or subsequent treatment options. There is an urgent and increasing need for well designed, large, prospective studies measuring the effect of different diagnostic approaches. Ultimately, this will help to inform the development of guidelines and tailor clinical practice for the benefit of patients.

Cellular sources and secretion mechanisms of IL‐36γ in response to recombinant bacterial components and whole bacteria. Interleukin‐36 is a family of novel interleukin‐1‐like proinflammatory cytokines that are highly expressed in epithelial tissues and several myeloid‐derived cell types. Like those of classic interleukin‐1 cytokines, the secretion mechanisms of interleukin‐36 are not well understood. Interleukin‐36γ secretion in dermal epithelial cells requires adenosine 5'‐triphosphate, which suggests a nonclassical mechanism of secretion. In this study, murine pulmonary macrophages and human alveolar macrophages were treated with recombinant pathogen‐associated molecular patterns (intact bacteria: Klebsiella pneumoniaeor Streptococcus pneumoniae). Cell lysates were analyzed for messenger ribonucleic acid by quantitative real‐time polymerase chain reaction, and conditioned medium was analyzed for interleukin‐36γ by enzyme‐linked immunosorbent assay, with or without sonication. In addition, conditioned medium was ultracentrifuged at 25,000 gand 100,000 g, to isolate microparticles and exosomes, respectively, and interleukin‐36γ protein was assessed in each fraction by Western blot analysis. Interleukin‐36γ mRNA was induced in both murine and human lung macrophages by a variety of pathogen‐associated molecular patterns, as well as heat‐killed and live Klebsiella pneumoniaeand Streptococcus pneumoniae, and induction occurred in a myeloid differentiation response gene 88–dependent manner. Secretion of interleukin‐36γ protein was enhanced by adenosine 5'‐triphosphate. Furthermore, extracellular interleukin‐36γ protein detection was markedly enhanced by sonication to disrupt membrane‐bound structures. Interleukin‐36γ protein was detected by Western blot in microparticles and exosome fractions isolated by ultracentrifugation. Interleukin‐36γ was induced and secreted from lung macrophages in response to Gram‐negative and ‐positive bacterial stimulation. The results suggest that interleukin‐36γ is secreted in a non‐Golgi–dependent manner by lung macrophages in response to Gram‐positive and ‐negative bacterial challenge.

Myofibroblasts are crucial to the pathogenesis of tissue fibrosis. Their formation of stress fibers results in the release of myocardin-related transcription factor (MRTF), a transcriptional coactivator of serum response factor (SRF). MRTF-A (Mkl1)-deficient mice are protected from lung fibrosis. We hypothesized that the SRF/MRTF pathway inhibitor CCG-203971 would modulate myofibroblast function in vitroand limit lung fibrosis in vivo. Normal and idiopathic pulmonary fibrosis lung fibroblasts were treated with/without CCG-203971 (N-[4-chlorophenyl]-1-[3-(2-furanyl)benzoyl]-3-piperidine carboxamide) and/or Fas-activating antibody in the presence/absence of transforming growth factor (TGF)-β1, and apoptosis was assessed. In vivostudies examined the effect of therapeutically administered CCG-203971 on lung fibrosis in two distinct murine models of fibrosis induced by bleomycin or targeted type II alveolar epithelial injury. In vitro, CCG-203971 prevented nuclear localization of MRTF-A; increased the apoptotic susceptibility of normal and idiopathic pulmonary fibrosis fibroblasts; blocked TGF-β1–induced myofibroblast differentiation; and inhibited TGF-β1–induced expression of fibronectin, X-linked inhibitor of apoptosis, and plasminogen activator inhibitor-1. TGF-β1 did not protect fibroblasts or myofibroblasts from apoptosis in the presence of CCG-203971. In vivo, CCG-203971 significantly reduced lung collagen content in both murine models while decreasing alveolar plasminogen activator inhibitor-1 and promoting myofibroblast apoptosis. These data support a central role of the SRF/MRTF pathway in the pathobiology of lung fibrosis and suggest that its inhibition can help resolve lung fibrosis by promoting fibroblast apoptosis.

Respiratory disease is the third leading cause of death in the industrialized world. Consequently, the trachea, lungs, and cardiopulmonary vasculature have been the focus of extensive investigations. Recent studies have provided new information about the mechanisms driving lung development and differentiation. However, there is still much to learn about the ability of the adult respiratory system to undergo repair and to replace cells lost in response to injury and disease. This Review highlights the multiple stem/progenitor populations in different regions of the adult lung, the plasticity of their behavior in injury models, and molecular pathways that support homeostasis and repair.

The role of the lung microbiome in the pathogenesis of idiopathic pulmonary fibrosis is unknown. We investigated whether unique microbial signatures were associated with progression of idiopathic pulmonary fibrosis.

A hallmark of idiopathic pulmonary fibrosis (IPF) is excessive and disordered deposition of extracellular matrix. Although the lung extracellular matrix normally plays an essential role in development and maintenance of lung tissue through reciprocal interactions with resident cells, the disordered matrix in the diseased lung is increasingly recognized as an active and important contributor to IPF pathogenesis. This working group summary from a recently conducted National Heart, Lung, and Blood Institute strategic planning workshop for IPF research highlights recent advances, challenges, and opportunities in the study of matrix biology in IPF. Particular attention is given to the composition and mechanical properties of the matrix in normal and diseased lungs, and the biochemical and biomechanical influences exerted by pathological matrix. Recently developed model systems are also summarized as key tools for advancing our understanding of matrix biology in IPF. Emerging approaches to therapeutically target the matrix in preclinical and clinical settings are discussed, as are important concepts, such as alterations of the matrix with aging and the potential for the resolution of fibrosis. Specific recommendations for future studies in matrix biology of IPF are also proposed.

ABSTRACTThe global burden of schistosomiasis is significant, with fibrosis a major associated morbidity and the primary cause of mortality. We have previously shown that schistosomiasis during pregnancy upregulates proinflammatory cytokines in the cord blood. In this study, we extend these findings to include a large panel of fibrosis-associated markers. We developed a multiplex bead-based assay to measure the levels of 35 proteins associated with fibrosis. Cord blood from 109 neonates born to mothers residing in an area of Schistosoma japonicumendemicity was assessed for these molecules. Ten mediators were elevated in the cord blood from schistosome-infected pregnancies, including insulin-like growth factor 1 (IGF-1), tumor growth factor ß1 (TGF-ß1), connective tissue growth factor (CTGF), procollagen I carboxy-terminal propeptide (PICP), amino-telopeptide of type 1 collagen (ICTP), collagen VI, desmosine, matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinases 1 (TIMP-1), and TIMP-4. Many of these were also positively correlated with preterm birth (PICP, ICTP, MMP-2, TGF-ß1, desmosine, CTGF, TIMP-1). In addition, birth weight was 168 g lower for infants with detectable levels of CTGF than for those with CTGF levels below the level of detection. Maternal schistosomiasis results in upregulation of fibrosis-associated proteins in the cord blood of the neonate, a subset of which are also associated with adverse birth outcomes. As the first report of fibrosis-associated molecules altered in the newborn of infected mothers, this study has broad implications for the health of the fetus, stretching from gestation to adulthood.

Previous research in our laboratory has demonstrated that repeated intranasal exposure to Aspergillus fumigatus conidia in C57BL/6 mice results in a chronic pulmonary inflammatory response that reaches its maximal level after four challenges. The inflammatory response is characterized by eosinophilia, goblet cell metaplasia, and T helper TH2 cytokine production, which is accompanied by sustained interleukin-17 (IL-17) expression that persists even after the TH2 response has begun to resolve. TH17 cells could develop in mice deficient in gamma interferon (IFN-γ), IL-4, or IL-10. In the lungs of IL-17 knockout mice repeatedly challenged with A. fumigatus conidia, inflammation was attenuated (with the most significant decrease occurring in eosinophils), conidial clearance was enhanced, and the early transient peak of CD4+CD25+FoxP3+cells blunted. IL-17 appeared to play only a minor role in eosinophil differentiation in the bone marrow but a central role in eosinophil extravasation from the blood into the lungs. These observations point to an expanded role for IL-17 in driving TH2-type inflammation to repeated inhalation of fungal conidia.

ABSTRACTPrevious research in our laboratory has demonstrated that repeated intranasal exposure to Aspergillus fumigatusconidia in C57BL/6 mice results in a chronic pulmonary inflammatory response that reaches its maximal level after four challenges. The inflammatory response is characterized by eosinophilia, goblet cell metaplasia, and T helper TH2 cytokine production, which is accompanied by sustained interleukin-17 (IL-17) expression that persists even after the TH2 response has begun to resolve. TH17 cells could develop in mice deficient in gamma interferon (IFN-?), IL-4, or IL-10. In the lungs of IL-17 knockout mice repeatedly challenged with A. fumigatusconidia, inflammation was attenuated (with the most significant decrease occurring in eosinophils), conidial clearance was enhanced, and the early transient peak of CD4+CD25+FoxP3+cells blunted. IL-17 appeared to play only a minor role in eosinophil differentiation in the bone marrow but a central role in eosinophil extravasation from the blood into the lungs. These observations point to an expanded role for IL-17 in driving TH2-type inflammation to repeated inhalation of fungal conidia.

ABSTRACTPulmonary arterial remodeling is a pathological process seen in a number of clinical disease states, driven by inflammatory cells and mediators in the remodeled artery microenvironment. In murine models, Th2 cell-mediated immune responses to inhaled antigens, such as purified Aspergillusallergen, have been reported to induce remodeling of pulmonary arteries. We have previously shown that repeated intranasal exposure of healthy C57BL/6 mice to viable, resting Aspergillus fumigatusconidia leads to the development of chronic pulmonary inflammation and the coevolution of Th1, Th2, and Th17 responses in the lungs. Our objective was to determine whether repeated intranasal exposure to Aspergillusconidia would induce pulmonary arterial remodeling in this mixed Th inflammatory microenvironment. Using weekly intranasal conidial challenges, mice developed robust pulmonary arterial remodeling after eight exposures (but not after two or four). The process was partially mediated by CD4+T cells and by interleukin-4 (IL-4) production, did not require eosinophils, and was independent of gamma interferon (IFN-γ) and IL-17. Furthermore, remodeling could occur even in the presence of strong Th1 and Th17 responses. Rather than serving an anti-inflammatory function, IL-10 was required for the development of the Th2 response to A. fumigatusconidia. However, in contrast to previous studies of pulmonary arterial remodeling driven by the A. fumigatusallergen, viable conidia also stimulated pulmonary arterial remodeling in the absence of CD4+T cells. Remodeling was completely abrogated in IL-10−/−mice, suggesting that a second, CD4+T cell-independent, IL-10-dependent pathway was also driving pulmonary arterial remodeling in response to repeated conidial exposure.

Pulmonary arterial remodeling is a pathological process seen in a number of clinical disease states, driven by inflammatory cells and mediators in the remodeled artery microenvironment. In murine models, Th2 cell-mediated immune responses to inhaled antigens, such as purified Aspergillus allergen, have been reported to induce remodeling of pulmonary arteries. We have previously shown that repeated intranasal exposure of healthy C57BL/6 mice to viable, resting Aspergillus fumigatus conidia leads to the development of chronic pulmonary inflammation and the coevolution of Th1, Th2, and Th17 responses in the lungs. Our objective was to determine whether repeated intranasal exposure to Aspergillus conidia would induce pulmonary arterial remodeling in this mixed Th inflammatory microenvironment. Using weekly intranasal conidial challenges, mice developed robust pulmonary arterial remodeling after eight exposures (but not after two or four). The process was partially mediated by CD4+T cells and by interleukin-4 (IL-4) production, did not require eosinophils, and was independent of gamma interferon (IFN-γ) and IL-17. Furthermore, remodeling could occur even in the presence of strong Th1 and Th17 responses. Rather than serving an anti-inflammatory function, IL-10 was required for the development of the Th2 response to A. fumigatus conidia. However, in contrast to previous studies of pulmonary arterial remodeling driven by the A. fumigatus allergen, viable conidia also stimulated pulmonary arterial remodeling in the absence of CD4+T cells. Remodeling was completely abrogated in IL-10–/–mice, suggesting that a second, CD4+T cell-independent, IL-10-dependent pathway was also driving pulmonary arterial remodeling in response to repeated conidial exposure.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease that is characterized by excessive proliferation of fibroblasts. The lipid mediator prostaglandin E2(PGE2) has the capacity to limit fibrosis through its inhibition of numerous functions of these fibroblasts; however, in the setting of fibrosis, fibroblasts have been shown to be resistant to PGE2. We have linked such resistance to decreased expression levels of the E prostanoid 2 (EP2) receptor. In this study, in fibroblasts from both mice and humans with pulmonary fibrosis, we show that DNA hypermethylation is responsible for diminished EP2 expression levels and PGE2resistance. Bisulfite sequencing of the prostaglandin E receptor 2 gene (PTGER2) promoter revealed that fibrotic fibroblasts exhibit greater PTGER2methylation than nonfibrotic control cells. Treatment with the DNA methylation inhibitors 5-aza-2′-deoxycytidine and zebularine as well as DNA methyltransferase-specific siRNA decreased PTGER2methylation, increased EP2 mRNA and protein expression levels, and restored PGE2responsiveness in fibrotic fibroblasts but not in nonfibrotic controls. PTGER2promoter hypermethylation was driven by an increase in Akt signal transduction. In addition to results described for the PTGER2promoter, fibrotic fibroblasts also exhibited increased global DNA methylation. These findings demonstrate that the down-regulation of PTGER2and consequent PGE2resistance are both mediated by DNA hypermethylation; we identified increased Akt signal transduction as a novel mechanism that promotes DNA hypermethylation during fibrogenesis.

ABSTRACTAspergillus fumigatus, a ubiquitous airborne fungus, can cause invasive infection in immunocompromised individuals but also triggers allergic bronchopulmonary aspergillosis in a subset of otherwise healthy individuals repeatedly exposed to the organism. This study addresses a critical gap in our understanding of the immunoregulation in response to repeated exposure to A. fumigatusconidia. C57BL/6 mice were challenged intranasally with A. fumigatusconidia weekly, and leukocyte composition, activation, and cytokine production were examined after two, four, and eight challenges. Approximately 99% of A. fumigatusconidia were cleared within 24 h after inoculation, and repeated exposure to A. fumigatusconidia did not result in hyphal growth or accumulation of conidia with time. After 2 challenges, there was an early influx of neutrophils and regulatory T (Treg) cells into the lungs but minimal inflammation. Repeated exposure promoted sustained expansion of the draining lymph nodes, while the influx of eosinophils and other myeloid cells into the lungs peaked after four exposures and then decreased despite continued A. fumigatuschallenges. Goblet cell metaplasia and low-level fibrosis were evident during the response. Repeated exposure to A. fumigatusconidia induced T cell activation in the lungs and the codevelopment by four exposures of TH1, TH2, and TH17 responses in the lungs, which were maintained through eight exposures. Changes in CD4 T cell polarization or Tregnumbers did not account for the reduction in myeloid cell numbers later in the response, suggesting a non-T-cell regulatory pathway involved in dampening inflammation during repeated exposure to A. fumigatusconidia.

Aspergillus fumigatus, a ubiquitous airborne fungus, can cause invasive infection in immunocompromised individuals but also triggers allergic bronchopulmonary aspergillosis in a subset of otherwise healthy individuals repeatedly exposed to the organism. This study addresses a critical gap in our understanding of the immunoregulation in response to repeated exposure to A. fumigatus conidia. C57BL/6 mice were challenged intranasally with A. fumigatus conidia weekly, and leukocyte composition, activation, and cytokine production were examined after two, four, and eight challenges. Approximately 99% of A. fumigatus conidia were cleared within 24 h after inoculation, and repeated exposure to A. fumigatus conidia did not result in hyphal growth or accumulation of conidia with time. After 2 challenges, there was an early influx of neutrophils and regulatory T (Treg) cells into the lungs but minimal inflammation. Repeated exposure promoted sustained expansion of the draining lymph nodes, while the influx of eosinophils and other myeloid cells into the lungs peaked after four exposures and then decreased despite continued A. fumigatus challenges. Goblet cell metaplasia and low-level fibrosis were evident during the response. Repeated exposure to A. fumigatus conidia induced T cell activation in the lungs and the codevelopment by four exposures of TH1, TH2, and TH17 responses in the lungs, which were maintained through eight exposures. Changes in CD4 T cell polarization or Tregnumbers did not account for the reduction in myeloid cell numbers later in the response, suggesting a non-T-cell regulatory pathway involved in dampening inflammation during repeated exposure to A. fumigatus conidia.

Idiopathic pneumonia syndrome (IPS) refers to a diffuse, noninfectious, acute lung injury after hematopoietic stem cell transplantation. Historically, IPS is associated with respiratory failure and mortality rates exceeding 50%. Preclinical studies have implicated tumor necrosis factor-α as an important effector molecule in the development of disease. We studied the tumor necrosis factor-α inhibitor, etanercept, combined with corticosteroids in treating 15 patients (median age, 18 years; range, 1-60 years) with IPS. Eight of 15 patients required mechanical ventilation at therapy onset. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg (maximum 25 mg) twice weekly, for a maximum of 8 doses. Therapy was well tolerated with no infectious pulmonary complications noted. Ten of 15 patients had a complete response, defined as the ability to discontinue supplemental oxygen support during study therapy. The median time to complete response was 7 days (range, 3-18 days), with a day 28 survival of 73%. IPS onset was associated with elevations of several inflammatory proteins in the bronchoalveolar lavage fluid and plasma, and response to therapy correlated with reductions in pulmonary and systemic inflammation. The combination of etanercept and corticosteroids is safe and is associated with high response rates and improved survival in patients with IPS.

Idiopathic pneumonia syndrome (IPS) refers to a diffuse, noninfectious, acute lung injury after hematopoietic stem cell transplantation. Historically, IPS is associated with respiratory failure and mortality rates exceeding 50%. Preclinical studies have implicated tumor necrosis factor-α as an important effector molecule in the development of disease. We studied the tumor necrosis factor-α inhibitor, etanercept, combined with corticosteroids in treating 15 patients (median age, 18 years; range, 1-60 years) with IPS. Eight of 15 patients required mechanical ventilation at therapy onset. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg (maximum 25 mg) twice weekly, for a maximum of 8 doses. Therapy was well tolerated with no infectious pulmonary complications noted. Ten of 15 patients had a complete response, defined as the ability to discontinue supplemental oxygen support during study therapy. The median time to complete response was 7 days (range, 3-18 days), with a day 28 survival of 73%. IPS onset was associated with elevations of several inflammatory proteins in the bronchoalveolar lavage fluid and plasma, and response to therapy correlated with reductions in pulmonary and systemic inflammation. The combination of etanercept and corticosteroids is safe and is associated with high response rates and improved survival in patients with IPS.

Sarcoidosis is a systemic inflammatory disorder of unknown etiology. Although any organ may be involved, the lungs are most frequently affected. The clinical course of the disease is highly variable, with up to two-thirds of untreated patients experiencing spontaneous remission within 12 – 24 months of onset of symptoms. When therapy is required, corticosteroids are considered standard, but studies demonstrating their ability to modify the long-term outcome in this disease are lacking. Often, the myriad of adverse side effects of corticosteroids necessitate the addition of immunosuppressants, cytotoxic agents or biologic therapies to maintain disease remission. Unfortunately, optimal therapeutic regimens have not been described. Patients who do not respond to therapy often experience progressive fibrotic changes and end-organ damage, which ultimately may result in significant morbidity or death. Agents commonly used to treat patients with sarcoidosis and emerging therapeutic options are discussed.

Wegener granulomatosis (WG) is the most common of the pulmonary granulomatous vasculitides. Organ involvement characteristically includes the upper and lower respiratory tracts and kidney, but virtually any organ can be involved. Severity of WG varies greatly among patients, ranging from indolent, chronic disease to fulminant, fatal vasculitis. Similarly, the degree of organ involvement differs among patients; WG may involve only a single organ (typically the lungs or upper respiratory tract) or may involve multiple organs. Histologically, WG is defined by necrotizing vasculitis involving small vessels, “geographic” necrosis, and granulomatous inflammation. Therapeutic regimens for active WG are generally effective at inducing remissions, but relapses after discontinuation of therapy are common. Early, short-course induction treatment with cyclophosphamide and corticosteroids for generalized, multiorgan WG, followed by maintenance therapy with less toxic agents (eg, methotrexate, azathioprine) is recommended. Recent studies also suggest that methotrexate combined with corticosteroids may be adequate for inducing remission in non–life-threatening WG. For tracheobronchial/subglottic stenosis and for orbital involvement, alternative therapeutic modalities are discussed.

Patients with Pneumocystis pneumonia often develop respiratory failure after entry into medical care, and one mechanism for this deterioration may be increased alveolar epithelial cell injury. In vitro, we previously demonstrated that Pneumocystis is not cytotoxic for alveolar epithelial cells. In vivo, however, infection with Pneumocystis could increase susceptibility to injury by stressors that, alone, would be sublethal. We examined transient exposure to hyperoxia as a prototypical stress that does cause mortality in normal mice. Mice were depleted of CD4+ T cells and inoculated intratracheally with Pneumocystis. Control mice were depleted of CD4+ T cells but did not receive Pneumocystis. After 4 weeks, mice were maintained in normoxia, were exposed to hyperoxia for 4 days, or were exposed to hyperoxia for 4 days followed by return to normoxia. CD4-depleted mice with Pneumocystis pneumonia demonstrated significant mortality after transient exposure to hyperoxia, while all uninfected control mice survived this stress. We determined that organism burdens were not different. However, infected mice exposed to hyperoxia and then returned to normoxia demonstrated significant increases in inflammatory cell accumulation and lung cell apoptosis. We conclude that Pneumocystis pneumonia leads to increased mortality following a normally sublethal hyperoxic insult, accompanied by alveolar epithelial cell injury and increased pulmonary inflammation.

ABSTRACTPatients with Pneumocystis pneumonia often develop respiratory failure after entry into medical care, and one mechanism for this deterioration may be increased alveolar epithelial cell injury. In vitro, we previously demonstrated that Pneumocystisis not cytotoxic for alveolar epithelial cells. In vivo, however, infection with Pneumocystiscould increase susceptibility to injury by stressors that, alone, would be sublethal. We examined transient exposure to hyperoxia as a prototypical stress that does cause mortality in normal mice. Mice were depleted of CD4+T cells and inoculated intratracheally with Pneumocystis. Control mice were depleted of CD4+T cells but did not receive Pneumocystis. After 4 weeks, mice were maintained in normoxia, were exposed to hyperoxia for 4 days, or were exposed to hyperoxia for 4 days followed by return to normoxia. CD4-depleted mice with Pneumocystispneumonia demonstrated significant mortality after transient exposure to hyperoxia, while all uninfected control mice survived this stress. We determined that organism burdens were not different. However, infected mice exposed to hyperoxia and then returned to normoxia demonstrated significant increases in inflammatory cell accumulation and lung cell apoptosis. We conclude that Pneumocystispneumonia leads to increased mortality following a normally sublethal hyperoxic insult, accompanied by alveolar epithelial cell injury and increased pulmonary inflammation.

Leptin is a pleiotropic hormone-cytokine known to regulate energy homeostasis and immune function. Neutrophils from leptin-deficient mice exhibited impaired phagocytosis of Klebsiella pneumoniae opsonized with serum containing complement and reduced CD11b expression that could be restored with exogenous leptin. These results suggest that leptin is required for normal neutrophil complement-mediated phagocytosis of bacteria.

ABSTRACTLeptin is a pleiotropic hormone-cytokine known to regulate energy homeostasis and immune function. Neutrophils from leptin-deficient mice exhibited impaired phagocytosis of Klebsiella pneumoniaeopsonized with serum containing complement and reduced CD11b expression that could be restored with exogenous leptin. These results suggest that leptin is required for normal neutrophil complement-mediated phagocytosis of bacteria.

Inflammatory and fibrotic processes can involve the small airways (i.e., respiratory and terminal bronchioles) in several connective tissue disorders (CTDs). Obliterative (constrictive) bronchiolitis (OB) as well cryptogenic organizing pneumonia (COP), previously termed bronchiolitis obliterans with organizing pneumonia (BOOP), are well-recognized, albeit rare, complications of rheumatoid arthritis and other CTDs. Bronchiectasis has also been described in patients with CTDs. Among the various pathologic conditions, clinical, radiographic, and histologic features and prognosis differ markedly. Clinical features are often nonspecific, and sometimes patients may be asymptomatic. Diagnosing these disorders may be difficult. High-resolution computed tomography (HRCT) is useful in detecting bronchiolar pathology, even when symptoms are minimal or absent. Surgical (open or thoracoscopic) lung biopsies can substantiate the diagnosis, but in some cases, the diagnosis can be affirmed less aggressively by appropriate imaging studies (e.g., HRCT) and transbronchial lung biopsies. Corticosteroids are highly efficacious for COP, but therapeutic options for OB are disappointing. Prophylactic antibiotics and good pulmonary hygiene remain the mainstay of therapy for patients with bronchiectasis.

Chitinase 3–like 1 protects against lung injury but has a profibrotic role during the repair phase.

FibronectinEDAis an endogenous TLR4 ligand in scleroderma.

By promoting actin depolymerization, the protein phosphatase activity of PTEN impairs macrophage phagocytosis of a fungal pathogen.