ABSTRACT
Respiratory viral infections are frequent in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) and can potentially progress to lower respiratory tract infection (LRTI). The intestinal microbiota contributes to resistance against viral and bacterial pathogens in the lung. However, whether intestinal microbiota composition and associated changes in microbe-derived metabolites contribute to the risk of LRTI following upper respiratory tract viral infection remains unexplored in the setting of allo-HCT. Fecal samples from 360 allo-HCT patients were collected at the time of stem cell engraftment and subjected to deep, 16S ribosomal RNA gene sequencing to determine microbiota composition, and short-chain fatty acid levels were determined in a nested subset of fecal samples. The development of respiratory viral infections and LRTI was determined for 180 days following allo-HCT. Clinical and microbiota risk factors for LRTI were subsequently evaluated using survival analysis. Respiratory viral infection occurred in 149 (41.4%) patients. Of those, 47 (31.5%) developed LRTI. Patients with higher abundances of butyrate-producing bacteria were fivefold less likely to develop viral LRTI, independent of other factors (adjusted hazard ratio = 0.22, 95% confidence interval 0.04-0.69). Higher representation of butyrate-producing bacteria in the fecal microbiota is associated with increased resistance against respiratory viral infection with LRTI in allo-HCT patients.
Subject(s)
Bacteria/metabolism , Butyrates/metabolism , Gastrointestinal Microbiome , Hematopoietic Stem Cell Transplantation/adverse effects , Respiratory Tract Infections/etiology , Respiratory Tract Infections/microbiology , Virus Diseases/etiology , Virus Diseases/microbiology , Adult , Feces/microbiology , Female , Humans , Male , Middle Aged , Protective Factors , Respiratory Tract Infections/metabolism , Transplantation, Homologous/adverse effects , Virus Diseases/metabolismABSTRACT
BACKGROUND: Serum (1,3)-beta-D glucan (BDG) is increasingly used to guide the management of suspected Pneumocystis pneumonia (PCP). BDG lacks specificity for PCP, and its clinical performance in high-risk cancer patients has not been fully assessed. Polymerase chain reaction (PCR) for PCP detection is highly sensitive, but cannot differentiate between colonization and infection. We evaluated the diagnostic performance of serum BDG in conjunction with PCP PCR on respiratory samples in patients with cancer and unexplained lung infiltrates. METHODS: We performed a retrospective analysis of adult patients evaluated for PCP at our institution from 2012 to 2015, using serum BDG and PCP PCR. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the serum BDG at different thresholds were evaluated using PCP PCR alone or in conjunction with clinical presentation in PCP PCR-positive patients. RESULTS: With PCP PCR alone as the reference method, BDG (≥80 pg/mL) had a sensitivity of 69.8%, specificity of 81.2%, PPV of 34.6%, and NPV of 95.2% for PCP. At ≥200 pg/mL in patients with a positive PCR and a compatible PCP clinical syndrome, BDG had a sensitivity of 70%, specificity of 100%, PPV of 100%, and NPV of 52.0% for PCP. CONCLUSIONS: Patients negative by both BDG and PCR were unlikely to have PCP. In patients with a compatible clinical syndrome for PCP, higher BDG values (>200 pg/mL) were consistently associated with clinically-significant PCP infections among PCP PCR-positive oncology patients.
Subject(s)
Neoplasms/complications , Pneumocystis carinii/isolation & purification , Pneumonia, Pneumocystis/diagnosis , beta-Glucans/blood , DNA, Fungal/analysis , Female , Humans , Male , Middle Aged , Pneumocystis carinii/genetics , Pneumonia, Pneumocystis/complications , Pneumonia, Pneumocystis/microbiology , Real-Time Polymerase Chain Reaction , Reproducibility of Results , Retrospective Studies , Sensitivity and SpecificityABSTRACT
OBJECTIVE: The aims of this study were to describe the computed tomographic features of organizing pneumonia (OP) in an oncologic patient population and to also identify features associated with lung cancer and patients undergoing hematopoietic stem cell transplant (HSCT). METHODS: In retrospective computed tomographies from 151 patients with pathologically confirmed OP between January 2009 and September 2014, number of lesions, location, size, margin type, and consistency, as well as volume of lymphadenopathy and the presence and size of pleural effusions, were recorded. Associated malignancy was noted. RESULTS: Organizing pneumonia most commonly presented as a diffuse process (n = 62, 41%), frequently occupied both a central and peripheral location (n = 79, 53%), and commonly presented with a solid appearance (n = 67, 44%) or with ground glass opacity (n = 80, 53%). Pleural effusions were seen in 68 patients (45%). Organizing pneumonia less frequently contained air bronchograms, cavitation, necrosis, surrounding ground glass opacity, or adjacent bronchiectasis. In patients with lung cancer (n = 25, 17%), OP more likely presented as discrete lesions and occupied a peripheral location as compared with patients with other malignancies (Ps = 0.025 and 0.002). In HSCT patients (n = 29, 19%), a diffuse process was more commonly seen than in non-HSCT patients (P = 0.038). CONCLUSIONS: Organizing pneumonia more commonly presents as discrete lesions with a peripheral location in patients with lung cancer and as a diffuse process in patients who had undergone HSCT.
Subject(s)
Cryptogenic Organizing Pneumonia/complications , Cryptogenic Organizing Pneumonia/diagnostic imaging , Lung Neoplasms/complications , Tomography, X-Ray Computed , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Hematopoietic Stem Cell Transplantation , Humans , Lung/diagnostic imaging , Lung Neoplasms/therapy , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
RATIONALE: Pulmonary complications (PCs) cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). Shifts in gut microbiota have been linked to HCT outcomes; however, their effect on PCs is unknown. OBJECTIVES: To investigate whether changes in gut microbiota are associated with PCs after HCT. METHODS: A single-center observational study was performed on 94 patients who underwent HCT from 2009 to 2011 and who were previously enrolled in a protocol for 16S ribosomal RNA sequencing of fecal microbiota. The primary endpoint, PC, was defined by new abnormal parenchymal findings on chest imaging in the setting of respiratory signs and/or symptoms. Outcomes were collected up to 40 months after transplant. Clinical and microbiota risk factors for PCs and mortality were evaluated using survival analysis. MEASUREMENTS AND MAIN RESULTS: One hundred twelve PCs occurred in 66 (70.2%) subjects. A high comorbidity index (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.30-4.00; P = 0.004), fluoroquinolones (HR, 2.29, 95% CI, 1.32-3.98; P = 0.003), low baseline diversity (HR, 2.63; 95% CI, 1.22-5.32; P = 0.015), and γ-proteobacteria domination of fecal microbiota (HR, 2.64; 95% CI, 1.10-5.65; P = 0.031), which included common respiratory pathogens, predicted PCs. In separate analyses, low baseline diversity was associated with PCs that occurred preengraftment (HR, 6.30; 95% CI, 1.42-31.80; P = 0.016), whereas γ-proteobacteria domination predicted PCs postengraftment (HR, 3.68; 95% CI, 1.49-8.21; P = 0.006) and overall mortality (HR, 3.52; 95% CI, 1.28-9.21; P = 0.016). Postengraftment PCs were also independent predictors of death (HR, 2.50; 95% CI, 1.25-5.22; P = 0.009). CONCLUSIONS: This is the first study to demonstrate prospective changes in gut microbiota associated with PCs after HCT. Postengraftment PCs and γ-proteobacteria domination were predictive of mortality. This suggests an adverse relationship between the graft and lung, which is perhaps mediated by bacterial composition in the gut. Further study is warranted.
Subject(s)
Gastrointestinal Microbiome , Hematologic Neoplasms/surgery , Hematopoietic Stem Cell Transplantation/adverse effects , Lung Diseases/etiology , Adult , Feces/microbiology , Female , Hematologic Neoplasms/complications , Hematologic Neoplasms/mortality , Hematopoietic Stem Cell Transplantation/mortality , High-Throughput Nucleotide Sequencing , Humans , Lung Diseases/microbiology , Lung Diseases/mortality , Male , Middle Aged , Predictive Value of Tests , Proportional Hazards Models , Prospective Studies , Risk Factors , Transplantation, Homologous/adverse effects , Transplantation, Homologous/mortalityABSTRACT
IgG4-related disease is a newly described systemic fibroinflammatory process, characterized by increase in IgG4-positive plasma cells. Its pathogenesis, including the role of IgG4, remains poorly understood. Plasma cell myeloma is typically associated with a large monoclonal serum spike, which is frequently of IgG isotype. We sought to identify and characterize a subset of IgG4-secreting myeloma, as it may provide a biological model of disease with high serum levels of IgG4. Six out of 158 bone marrow biopsies (4%) from patients with IgG myeloma expressed IgG4. Four patients were men and two were women, with a mean age of 64 (range 53-87) years. Imaging showed fullness of pancreatic head (1), small non-metabolic lymphadenopathy (1), and bone lytic lesions (6). Two patients developed necrotizing fasciitis. All had elevated serum M-protein (mean 2.4, range 0.5-4.2 g/dl), and none had definite signs or symptoms of IgG4-related disease. Four myelomas had plasmablastic morphology. Four had kappa and two had lambda light chain expression. Three cases expressed CD56. Two patients had a complex karyotype. In conclusion, the frequency of IgG4 myeloma correlates with the normal distribution of IgG4 isoform. The patients with IgG4 myeloma appear to have a high rate of plasmablastic morphology and could be predisposed to necrotizing fasciitis. Despite high serum levels of IgG4, none had evidence of IgG4-related disease. These findings suggest that the increased number of IgG4-positive plasma cells is not the primary etiologic agent in IgG4-related disease. Elevated serum levels of IgG4 is not sufficient to produce the typical disease presentation and should not be considered diagnostic of IgG4-related disease.
Subject(s)
Immunoglobulin G/immunology , Multiple Myeloma/immunology , Multiple Myeloma/pathology , Aged , Aged, 80 and over , Female , Humans , Immunoglobulin G/blood , Male , Middle Aged , Multiple Myeloma/bloodABSTRACT
BACKGROUND AND PURPOSE: Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP. MATERIALS AND METHODS: We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes. RESULTS: Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-ß1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01-1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1-1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89-1, p = 0.036). CONCLUSION: We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.
Subject(s)
Biomarkers , Indoles , Radiation Pneumonitis , Humans , Radiation Pneumonitis/etiology , Radiation Pneumonitis/blood , Male , Indoles/therapeutic use , Female , Biomarkers/blood , Aged , Middle Aged , Lung Neoplasms/radiotherapy , Lung Neoplasms/drug therapy , Disease ProgressionABSTRACT
RATIONALE: Sarcoidosis is an idiopathic granulomatous disorder with heterogeneous clinical manifestations and variable prognosis. Monitoring disease activity is important to identify patients requiring treatment. Several cytokines have previously been shown to be elevated in the serum of patients with sarcoidosis and may be useful biomarkers of disease activity. OBJECTIVES: To identify novel biomarkers of sarcoidosis disease activity. To identify the relationship between plasma cytokines, disease severity and prognosis. METHODS: The study was approved by the institutional review board. Plasma concentration of 19 cytokines was measured in 112 subjects with chronic sarcoidosis and 52 matched controls, using the bead-based Milliplex xMAP multiplex technology. Plasma levels of individual cytokines were compared between the two groups, and between the groups with clinically active vs. inactive disease. Sensitivity, specificity and receiver operating characteristics curves were used to evaluate biomarker performance. Linear regression analyses were performed to identify associations between cytokine levels, pulmonary function tests and changes in pulmonary function. MEASUREMENTS AND MAIN RESULTS: Subjects with sarcoidosis had higher plasma levels of interferon gamma induced protein 10 (IP-10) and tumor necrosis factor α (TNFα). IP-10 had the highest sensitivity and specificity in identifying active disease. Higher levels of IP-10 and TNFα were associated with greater disease severity and better prognosis. CONCLUSIONS: IP-10 is a potentially useful biomarker of sarcoidosis and its severity.
Subject(s)
Chemokine CXCL10/blood , Sarcoidosis/blood , Adult , Biomarkers/blood , Cytokines/blood , Epidermal Growth Factor/blood , Female , Humans , Male , Middle Aged , Prognosis , Sarcoidosis/metabolism , Tumor Necrosis Factor-alpha/bloodABSTRACT
BACKGROUND: Receptors for advanced glycation end-products (RAGE) are cell surface receptors prominently expressed by lung epithelium. Previous research demonstrated that over-expression of RAGE by murine alveolar epithelial cells during embryogenesis caused severe lung hypoplasia and neonatal lethality. However, the effects of RAGE over-expression on adjacent matrix and endothelial cells remained unknown. METHODS: RAGE transgenic (TG) mice were generated that conditionally over-expressed RAGE in alveolar type II cells when fed doxycycline (dox) from conception to E18.5. To evaluate effects on the basement membrane, immunostaining and immunoblotting were performed for collagen IV and MMP-9, a matrix metalloprotease capable of degrading basement membranes. To assess changes in vasculature, immunostaining, immunoblotting and qRT-PCR were performed for Pecam-1, a platelet endothelial cell adhesion marker also known as CD31. Lastly, to characterize potential regulatory mechanisms of endothelial cell differentiation, immunoblotting and qRT-PCR for FoxM1, a key endothelium-specific transcription factor of the Forkhead Box (Fox) family, were completed. RESULTS: Qualitative immunostaining for collagen IV was less in RAGE TG mice compared to controls and immunoblotting revealed decreased collagen IV in the RAGE TG mouse lung. Additionally, elevated MMP-9 detected via immunostaining and immunoblotting implicated MMP-9 as a possible down stream effector in matrix destabilization mediated by RAGE signaling. Lastly, Pecam-1 assessment revealed a decrease in the prevalence of microvascular endothelial cells coincident with FoxM1 abrogation in RAGE TG mice compared to controls. CONCLUSIONS: RAGE over-expression by alveolar epithelium weakened the basement membrane and associated matrix via increased MMP-9 activity. Furthermore, over-expression of RAGE inhibited FoxM1, suggesting that anomalous transcriptional control contributes to decreased endothelial cell prevalence in the TG mouse lung.
Subject(s)
Basement Membrane/metabolism , Endothelium/pathology , Pulmonary Alveoli/embryology , Pulmonary Alveoli/metabolism , Receptors, Immunologic/metabolism , Animals , Cell Differentiation/physiology , Collagen/metabolism , Endothelium/metabolism , Epithelium/embryology , Epithelium/metabolism , Forkhead Transcription Factors/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Animal , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Receptor for Advanced Glycation End Products , Receptors, Immunologic/geneticsABSTRACT
This study aims to evaluate the predictive value of routine pulmonary function testing (PFT) at the 12-month mark post-autologous hematopoietic cell transplant (AHCT) in identifying clinically significant lung disease in lymphoma survivors. In 247 patients, 173 (70%) received BEAM (carmustine, etoposide, cytarabine, melphalan), and 49 (20%) received TBC (thiotepa, busulfan, cyclophosphamide) conditioning regimens. Abnormal baseline PFT was noted in 149 patients (60%). Thirty-four patients had a significant decline (reduction of >/= 20% in DLCO or FEV1 or FVC) in post-AHCT PFT, with the highest incidence in the CNS lymphoma group (39%). The incidence of clinically significant lung disease post-transplant was low at 2% and there was no association between abnormal pre- and 1-year post-transplant PFTs with the development of clinical lung disease. While this study illustrates the impact of treatment regimens on PFT changes, it did not demonstrate a predictive value of scheduled PFTs in identifying clinically significant post-AHCT lung disease.
Subject(s)
Hematopoietic Stem Cell Transplantation , Lung Diseases , Lymphoma, Non-Hodgkin , Lymphoma , Humans , Hematopoietic Stem Cell Transplantation/adverse effects , Lymphoma/therapy , Lymphoma/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Carmustine/therapeutic use , Etoposide/adverse effects , Melphalan/therapeutic use , Transplantation, Autologous , Transplantation Conditioning/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
PURPOSE: Radiation pneumonitis (RP) is the most common dose-limiting toxicity for thoracic radiation therapy. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis, which shares pathophysiological pathways with the subacute phase of RP. Our goal was to investigate the efficacy and safety of nintedanib added to a prednisone taper compared with a prednisone taper alone in reducing pulmonary exacerbations in patients with grade 2 or higher (G2+) RP. METHODS AND MATERIALS: In this phase 2, randomized, double-blinded, placebo-controlled trial, patients with newly diagnosed G2+ RP were randomized 1:1 to nintedanib or placebo in addition to a standard 8-week prednisone taper. The primary endpoint was freedom from pulmonary exacerbations at 1 year. Secondary endpoints included patient-reported outcomes and pulmonary function tests. Kaplan-Meier analysis was used to estimate the probability of freedom from pulmonary exacerbations. The study was closed early due to slow accrual. RESULTS: Thirty-four patients were enrolled between October 2015 and February 2020. Of 30 evaluable patients, 18 were randomized to the experimental Arm A (nintedanib + prednisone taper) and 12 to the control Arm B (placebo + prednisone taper). Freedom from exacerbation at 1 year was 72% (confidence interval, 54%-96%) in Arm A and 40% (confidence interval, 20%-82%) in Arm B (1-sided, P = .037). In Arm A, there were 16 G2+ adverse events possibly or probably related to treatment compared with 5 in the placebo arm. There were 3 deaths during the study period in Arm A due to cardiac failure, progressive respiratory failure, and pulmonary embolism. CONCLUSIONS: There was an improvement in pulmonary exacerbations by the addition of nintedanib to a prednisone taper. Further investigation is warranted for the use of nintedanib for the treatment of RP.
Subject(s)
Protein Kinase Inhibitors , Radiation Pneumonitis , Humans , Protein Kinase Inhibitors/therapeutic use , Radiation Pneumonitis/etiology , Prednisone/adverse effects , Disease Progression , Double-Blind MethodABSTRACT
Individual comorbidities have distinct contributions to nonrelapse mortality (NRM) following allogeneic hematopoietic cell transplantation (allo-HCT). We studied the impact of comorbidities individually and in combination in a single-center cohort of 573 adult patients who underwent CD34-selected allo-HCT following myeloablative conditioning. Pulmonary disease, moderate to severe hepatic comorbidity, cardiac disease of any type, and renal dysfunction were associated with increased NRM in multivariable Cox regression models. A Simplified Comorbidity Index (SCI) composed of the 4 comorbidities predictive of NRM, as well as age >60 years, stratified patients into 5 groups with a stepwise increase in NRM. NRM rates ranged from 11.4% to 49.9% by stratum, with adjusted hazard ratios of 1.84, 2.59, 3.57, and 5.38. The SCI was also applicable in an external cohort of 230 patients who underwent allo-HCT with unmanipulated grafts following intermediate-intensity conditioning. The area under the receiver operating characteristic curve (AUC) of the SCI for 1-year NRM was 70.3 and 72.0 over the development and external-validation cohorts, respectively; corresponding AUCs of the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) were 61.7 and 65.7. In summary, a small set of comorbidities, aggregated into the SCI, is highly predictive of NRM. The new index stratifies patients into distinct risk groups, was validated in an external cohort, and provides higher discrimination than does the HCT-CI.
Subject(s)
Hematopoietic Stem Cell Transplantation , Adult , Comorbidity , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Middle Aged , Proportional Hazards Models , Transplantation Conditioning , Transplantation, HomologousABSTRACT
Pulmonary complications (PC) of hematologic malignancies and their treatments are common causes of morbidity and mortality. Early diagnosis is challenging due to host risk factors, clinical instability, and provider preference. Delayed diagnosis impairs targeted treatment and may contribute to poor outcomes. An integrated understanding of clinical risk and radiographic patterns informs a timely approach to diagnosis and treatment. There is little prospective evidence guiding optimal modality and timing of minimally invasive lung sampling; however, a low threshold for diagnostic bronchoscopy during the first 24 to 72 hours after presentation should be a guiding principle in high-risk patients.
Subject(s)
Hematologic Neoplasms/complications , Hematopoietic Stem Cell Transplantation/adverse effects , Lung Diseases/diagnosis , Lung/pathology , Transplantation Conditioning/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Prospective Studies , Transplantation Conditioning/methodsABSTRACT
BACKGROUND: Gemcitabine-related pneumonitis (GRP) has been reported relatively frequently for pancreas cancer in the literature; however, underlying risk factors and optimal management remain to be defined. We studied a cohort of patients with GRP and investigated potential predisposing factors in pancreatic cancer patients. PATIENTS AND METHODS: A total 2440 patients at Memorial Sloan Kettering Cancer Center were identified between January 1, 2000, and December 31, 2012, and were screened for grade 2 or higher GRP in an institutional tumor registry and using an ICD billing code database. Demographic and clinical information was extracted by electronic chart review. RESULTS: A total of 28 patients (1.1%) with GRP were identified. Incidence of grade 2, 3, and 4 reactions were 7 (25%), 18 (64%), and 3 (11%), respectively. No GRP-related mortality was observed. Twenty-one patients (75%) reported a history of cigarette smoking. Seventeen patients (61%) were alcohol users. Six patients (21%) were either regular or heavy drinkers. Most patients (93%) had either locally advanced or metastatic disease. Three patients (11%) underwent a diagnostic bronchoscopy, and in 1 patient a diagnosis of organizing pneumonia was established. Morbidity was significant; 3 patients (11%) required treatment in the intensive care unit. All hospitalized patients received steroid treatment. CONCLUSION: GRP is relatively uncommon but incurs significant morbidity. Potential risk factors include advanced-stage disease, along with smoking and alcohol consumption and possibly underlying lung disease. We recommend a high level of clinical alertness regarding the diagnosis, early pulmonary referral, and cessation of gemcitabine on suspicion of GRP.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Deoxycytidine/analogs & derivatives , Liver Neoplasms/drug therapy , Pancreatic Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Pneumonia/chemically induced , Adenocarcinoma/pathology , Adenocarcinoma/secondary , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Alcohol Drinking/epidemiology , Alcohol-Related Disorders/epidemiology , Capecitabine/administration & dosage , Cohort Studies , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Erlotinib Hydrochloride/administration & dosage , Female , Humans , Liver Neoplasms/secondary , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Pancreatic Neoplasms/pathology , Peritoneal Neoplasms/secondary , Pneumonia/drug therapy , Pneumonia/epidemiology , Retrospective Studies , Risk Factors , Severity of Illness Index , Smoking/epidemiology , GemcitabineABSTRACT
BACKGROUND: Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis. METHODS: Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-ß(1) on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model. RESULTS: Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-ß(1) inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-ß(1). In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of á-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of á-smooth muscle actin and fibronectin. CONCLUSION: Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-ß(1) may represent a mechanism for the promotion of fibrogenesis in IPF.