• advanced materials
• ciliopathy
• fibrosis
• graphene
• inhalation exposure
• primary human bronchial epithelial cell culture
• respiratory mucus

• Humans
• Immunity, Innate/drug effects
• Silicon Compounds/chemistry
• Silicon Compounds/pharmacology
• Silicon Compounds/toxicity
• Epithelial Cells/drug effects
• Epithelial Cells/immunology
• Epithelial Cells/cytology
• Nanowires/chemistry
• Nanowires/toxicity
• Mucociliary Clearance/drug effects
• Mucociliary Clearance/immunology
• Bronchi/cytology
• Bronchi/immunology
• Bronchi/drug effects
• Carbon Compounds, Inorganic/chemistry
• Carbon Compounds, Inorganic/pharmacology
• Carbon Compounds, Inorganic/toxicity
• Cells, Cultured

• European Commission
• Staatssekretariat f?r Bildung, Forschung und Innovation

• Biodistribution
• Biomarker
• Biomonitoring
• Crystalline silica
• Exposure
• Particle translocation
• Silicon

• Silicon Dioxide/pharmacokinetics
• Silicon Dioxide/metabolism
• Silicon Dioxide/analysis
• Silicon Dioxide/urine
• Animals
• Mice
• Tissue Distribution
• Occupational Exposure/analysis
• Biological Monitoring/methods
• Inhalation Exposure/analysis
• Humans
• Male
• Lung/metabolism
• Mass Spectrometry
• Air Pollutants, Occupational

• Autoimmunity
• Crystalline silica
• Environment
• Immunity
• Macrophages

• Silicon Dioxide/adverse effects
• Silicon Dioxide/immunology
• Humans
• Animals
• Epithelial Cells/immunology
• Epithelial Cells/drug effects
• Epithelial Cells/pathology
• Lung/immunology
• Lung/pathology
• Lung/drug effects
• Autoimmunity
• Silicosis/immunology
• Silicosis/therapy
• Silicosis/pathology
• Autoimmune Diseases/immunology
• Autoimmune Diseases/therapy
• Autoimmune Diseases/etiology
• Mice
• Immunity, Innate

• Autoimmunity
• Cancer
• Co-carcinogenicity
• Fibrosis
• Inflammation
• Quartz
• Respirable crystalline silica
• Silanols
• Silica

• Animals
• Quartz/toxicity
• Mice, Inbred C57BL
• Silanes/toxicity
• Silanes/chemistry
• Lung/drug effects
• Lung/immunology
• Lung/pathology
• Lung/metabolism
• Mice
• Inhalation Exposure
• Female
• Lung Neoplasms/chemically induced
• Lung Neoplasms/immunology
• Lung Neoplasms/pathology
• Male
• Pulmonary Fibrosis/chemically induced
• Pulmonary Fibrosis/immunology
• Pulmonary Fibrosis/pathology
• Pneumonia/chemically induced
• Pneumonia/immunology
• Pneumonia/metabolism
• Pneumonia/pathology
• Autoimmunity/drug effects

• Surface Silanols as Key Descriptor of the Silica Hazard European Association of Industrial Silica Producers (Brussels, Belgium)
• CUP: D13C22003520001 MUR Program "Dipartimenti di Eccellenza 2023-2027"
• ARC 19/24-098, CYTAID Actions de Recherche Concertées, Fédération Wallonie-Bruxelles
• 2022-193 Fondation contre le Cancer
• Contract no. 874707, Eximious European Commission
• MUR Program “Dipartimenti di Eccellenza 2023-2027”
• Fonds De La Recherche Scientifique - FNRS

• Humans
• Silicon Dioxide
• Silicosis
• Fibrosis
• Autophagy
• Cytokines

• Amosite fibers
• Autoimmunity
• Efferocytosis
• Lung fibrosis
• Macrophages

• Humans
• Mice
• Animals
• Asbestos, Amosite/pharmacology
• Asbestos, Amosite/toxicity
• Pulmonary Fibrosis/chemically induced
• Autoimmunity
• Interleukin-6/metabolism
• Lung/metabolism
• Macrophages
• DNA/metabolism

• cell surface marker
• extracellular matrix
• fibroblast subtype
• pulmonary fibrosis
• single-cell RNA-sequencing

• Humans
• Mice
• Animals
• COVID-19/metabolism
• Fibroblasts/metabolism
• Lung/pathology
• Idiopathic Pulmonary Fibrosis/pathology
• Fibrosis
• Membrane Proteins/metabolism

• R01 AI052201 NIAID NIH HHS
• P01 HL108793 NHLBI NIH HHS
• R35 HL150829 NHLBI NIH HHS
• National Institutes of Health

• drug delivery
• inflammation

• amorphous silica
• crystalline silica
• experimental studies
• lung
• nanoparticles
• particles
• quartz
• silica
• silicon dioxide
• toxicity

• COPD
• immune landscape
• lung cancer
• never-smoker
• smoker

• Adult
• Causality
• Cigarette Smoking/adverse effects
• Humans
• Lung Neoplasms/complications
• Pulmonary Disease, Chronic Obstructive/etiology
• Risk Factors
• Nicotiana

• Animals
• B-Lymphocytes/immunology
• Bleomycin/toxicity
• Collagen/metabolism
• Female
• Humans
• Idiopathic Pulmonary Fibrosis/chemically induced
• Idiopathic Pulmonary Fibrosis/immunology
• Idiopathic Pulmonary Fibrosis/pathology
• Lung/pathology
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Parenchymal Tissue/pathology
• T-Lymphocytes/immunology
• Transforming Growth Factor beta1/metabolism

• Coagulation cascade
• Drug therapy
• Fibroblast accumulation
• Idiopathic pulmonary fibrosis
• Immune activation
• PI3K/AKT signaling
• Pathogenesis
• Therapeutic target

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Immune disorders play an important role in IPF pathogenesis. Here, we show that Th9 cells differentiate and activate in the lung tissue of patients with IPF and bleomycin (BLM)-induced lung fibrosis mice. Moreover, we found that Th9 cells promote pulmonary fibrosis in two ways. On the one hand, Th9 cells promote fibroblast differentiation, activation, and collagen secretion by secreting IL-9. On the other hand, they promote differentiation of Th0 cells into Th2 cells by secreting IL-4. Th9 cells and Th2 cells can promote each other, accelerating the Th1/Th2 imbalance and eventually forming a positive feedback of pulmonary fibrosis. In addition, we found that neutralizing IL-9 in both preventive and therapeutic settings ameliorates bleomycin-induced pulmonary fibrosis. Furthermore, we identified several critical signaling pathways involved in the effect of neutralizing IL-9 on pulmonary fibrosis by proteomics study. From an immunological perspective, we elucidated the novel role and underlying mechanism of Th9 cells in pulmonary fibrosis. Our study suggested that Th9-based immunotherapy may be employed as a treatment strategy for IPF.

• Th2 cells
• Th9 cells
• idiopathic pulmonary fibrosis
• interleukin-9

Severe glomerular injury ultimately leads to tubulointerstitial fibrosis that determines patient outcome, but the immunological molecules connecting these processes remain undetermined. The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, plays a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. After acute glomerular injury using nephrotoxic serum, tubules in the VISTA-deficient (Vsir–/–) kidney suffered more damage than those in WT kidneys. When interstitial immune cells were examined, the contact frequency of macrophages with infiltrated T cells increased and the immunometabolic features of T cells changed to showing high oxidative phosphorylation and fatty acid metabolism and overproduction of IFN-γ. The Vsir–/– parenchymal tissue cells responded to this altered milieu of interstitial immune cells as more IL-9 was produced, which augmented tubulointerstitial fibrosis. Blocking antibodies against IFN-γ and IL-9 protected the above pathological process in VISTA-depleted conditions. In human samples with acute glomerular injury (e.g., antineutrophil cytoplasmic autoantibody vasculitis), high VISTA expression in tubulointerstitial immune cells was associated with low tubulointerstitial fibrosis and good prognosis. Therefore, VISTA is a sentinel protein expressed in kidney macrophages that prevents tubulointerstitial fibrosis via the IFN-γ/IL-9 axis after acute antibody-mediated glomerular injury.

• Fibrosis
• Macrophages
• Nephrology
• T cells

• cytokine biology
• interstitial fibrosis

• Cytokines
• Disease Progression
• Humans
• Idiopathic Interstitial Pneumonias/diagnosis
• Idiopathic Interstitial Pneumonias/drug therapy
• Prognosis
• Retrospective Studies
• Thrombomodulin

• Japan Society for the Promotion of Science
• Japan Agency for Medical Research and Development
• National Hospital Organization

Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. Interleukin 9 (IL9) is a pleiotropic cytokine with pro- and anti-inflammatory functions. The aim of this study was to evaluate the therapeutic activity of F8IL9F8 consisting of IL9 fused to the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin, which is abundantly expressed in pulmonary vasculature and right ventricular myocardium in PH. Methods: The efficacy of F8IL9F8 in attenuating PH progression in the monocrotaline mouse model was evaluated in comparison to an endothelin receptor antagonist (ERA) or an IL9 based immunocytokine with irrelevant antibody specificity (KSFIL9KSF). Treatment effects were assessed by right heart catheterization, echocardiography as well as histological and immunohistochemical tissue analyses. Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group. Both, F8IL9F8 and ERA treatments lead to a significant reduction in RVPsys and an improvement of echocardiographic parameters when compared to the MCT group not observable for the KSFIL9KSF group. Only F8IL9F8 significantly reduced lung tissue damage and displayed a significant decrease of leukocyte and macrophage accumulation in the lungs and right ventricles. Conclusions: Our study provides first pre-clinical evidence for the use of F8IL9F8 as a new therapeutic agent for PH in terms of a disease-modifying concept addressing cardiovascular remodeling.

• fibronectin
• immunocytokines
• interleukin-9
• monocrotaline
• mouse
• pulmonary hypertension

• Animals
• Antibodies/chemistry
• CHO Cells
• Cricetulus
• Cytokines/metabolism
• Disease Models, Animal
• Drug Carriers
• Echocardiography
• Endothelin Receptor Antagonists/chemistry
• Hemodynamics
• Hypertension, Pulmonary/immunology
• Hypertension, Pulmonary/therapy
• Immunohistochemistry
• Inflammation
• Interleukin-9/administration & dosage
• Interleukin-9/therapeutic use
• Leukocytes/metabolism
• Lung/metabolism
• Macrophages/metabolism
• Mice
• Protein Binding
• Ventricular Function, Right

• ILC
• MDSC
• T helper
• Treg
• nanoparticle
• particle
• polarization of immune cells
• pulmonary inflammation and fibrosis

• Animals
• Cytokines/immunology
• Dendritic Cells/immunology
• Humans
• Immune Tolerance
• Immunity, Cellular
• Inflammation/immunology
• Inflammation/pathology
• Inhalation
• Lung/immunology
• Lung/pathology
• Lymphocytes/immunology
• Macrophages/immunology
• Myeloid-Derived Suppressor Cells/immunology
• Particulate Matter/adverse effects
• Particulate Matter/immunology
• Signal Transduction/immunology
• T-Lymphocyte Subsets/immunology

Cymbopogon giganteus Chiov. (Poaceae) is a medicinal plant used to treat various diseases in traditional medicine in several African countries. The present study aims to evaluate the oral and inhalation toxicity as well as the mutagenic effects of the essential oil of Cymbopogon giganteus leaves (EOCG) from a sample collected in Benin. Mutagenic potential was assessed by the Ames test using Salmonella typhimurium strains TA98 and TA100. Oral acute toxicity was carried out by administration of a single dose of 2000 mg/kg b.w. to Wistar rats while oral subacute toxicity was assessed by daily administration of 50 and 500 mg/kg of EOCG for 28 days. Finally, inhalation toxicity was assessed by administration of a single dose of 0.125%, 0.5%, 2% or 5% v/v of EOCG emulsions in 0.05% v/v lecithin solution in sterile water for the first experiment, and in a second one by administration of single dose of 0.125% or 0.5% v/v. A broncho-alveolar lavage was performed after 3 h or 24 h, respectively. The results show that EOCG is not mutagenic on Salmonella typhimurium strains at the highest concentration tested (200 μg/plate). In the acute oral toxicity study, EOCG induce neither mortality nor toxicity, showing that the LD₅₀ is greater than 2000 mg/kg. The subacute oral toxicity study at both doses did not show any significant difference in body weight, relative organ weight, hematological and/or biochemical parameters or histopathology as compared to the control group. EOCG induced mortality and inflammation in lungs 3 h after administration of a single dose of 5% or 2% v/v. Single doses of 0.125% or 0.5% v/v did not induce inflammation, cell recruitment nor cytotoxicity in lungs 3 h or 24 h after administration, suggesting safety at these concentrations. This first report on the in vivo toxicity will be useful to guide safe uses of EOCG.

• IL-9
• fibrosis
• idiopathic pulmonary fibrosis
• mouse
• silica

Li-ion batteries (LIB) are increasingly used worldwide. They are made of low solubility micrometric particles, implying a potential for inhalation toxicity in occupational settings and possibly for consumers. LiCoO₂ (LCO), one of the most used cathode material, induces inflammatory and fibrotic lung responses in mice. LCO also stabilizes hypoxia-inducible factor (HIF) -1α, a factor implicated in inflammation, fibrosis and carcinogenicity. Here, we investigated the role of cobalt, nickel and HIF-1α as determinants of toxicity, and evaluated their predictive value for the lung toxicity of LIB particles in in vitro assays.

By testing a set of 5 selected LIB particles (LCO, LiNiMnCoO₂, LiNiCoAlO₂) with different cobalt and nickel contents, we found a positive correlation between their in vivo lung inflammatory activity, and (i) Co and Ni particle content and their bioaccessibility and (ii) the stabilization of HIF-1α in the lung. Inhibition of HIF-1α with chetomin or PX-478 blunted the lung inflammatory response to LCO in mice. In IL-1β deficient mice, HIF-1α was the upstream signal of the inflammatory lung response to LCO. In vitro, the level of HIF-1α stabilization induced by LIB particles in BEAS-2B cells correlated with the intensity of lung inflammation induced by the same particles in vivo.

We conclude that HIF-1α, stabilized in lung cells by released Co and Ni ions, is a mechanism-based biomarker of lung inflammatory responses induced by LIB particles containing Co/Ni. Documenting the Co/Ni content of LIB particles, their bioaccessibility and their capacity to stabilize HIF-1α in vitro can be used to predict the lung inflammatory potential of LIB particles.

The online version of this article (10.1186/s12989-019-0319-z) contains supplementary material, which is available to authorized users.

• Biomarker
• Cobalt
• IL-1β, Epithelial cells
• Nickel
• Predictive toxicology

• MKP-5
• fibroblast
• homeostasis
• kinase
• phosphatase
• pulmonary fibrosis

• Angiogenesis
• Interleukin-9
• Non-small cell lung cancer
• VEGF

Weight loss due to skeletal muscle atrophy in patients with chronic pulmonary disease is negatively correlated with clinical outcome. Pulmonary fibrosis is a chronic and progressive interstitial lung disease characterized by the dysregulated deposition of the extracellular matrix (ECM) with the destruction of normal tissue, resulting in end-stage organ failure. BLM-induced fibrosis is one of several different experimental models of pulmonary fibrosis, characterized by inflammation and excessive ECM deposition. We directly induced mouse lung injury by the intratracheal administration of bleomycin and monitored the physiological and biochemical changes in lung and skeletal muscle tissues by using lung function testing, ELISA, Western blotting, and immunohistochemistry. Here, we found that BLM-induced lung fibrosis with thickened interstitial lung tissue, including fibronectin and collagen, was correlated with the increased serum concentrations of IL-6 and IL-33 and accompanied by reduced lung function, including FRC (functional residual capacity), C chord (lung compliance), IC (inspiratory capacity), VC (vital capacity), TLC (total lung capacity), and FVC (forced vital capacity) (p < 0.05). The activity of AKT in lung tissue was suppressed, but conversely, the activity of STAT3 was enhanced during lung fibrosis in mice. In addition, we found that the amount of sST2, the soluble form of the IL-33 receptor, was dramatically decreased in lung fibrosis tissues. The skeletal muscle tissue isolated from lung injury mice increased the activation of STAT3 and AMPK, accompanied by an increased amount of Atrogin-1 protein in BLM-induced lung fibrosis mice. The mouse myoblast cell-based model showed that IL-6 and IL-33 specifically activated STAT3 and AMPK signaling, respectively, to induce the expression of the muscle-specific proteolysis markers MuRF1 and Atrogin-1. These data suggested that increased levels of IL-6 and IL-33 in the serum of mice with BLM-induced lung injury may cause lung fibrosis with thickened interstitial lung tissue accompanied by reduced lung function and muscle mass through the activation of STAT3 and AMPK signals.

• Animals
• Fibrosis
• Idiopathic Pulmonary Fibrosis
• Interleukin-9
• Mice
• Pneumonia
• Silicon Dioxide

• R01 AI111475 NIAID NIH HHS

• Ferruginous bodies.
• Fibrosis
• HIF-1α
• Inflammation
• Lung

• allergic inflammation
• asthma
• interleukin-9
• interleukin-9 receptor
• treatment

• B cells
• Eosinophils
• Epithelial cells
• IL-9
• Innate lymphoid cells
• Mast cells

• fibrosis
• lung
• lymphocytes
• pneumonitis
• radiotherapy

• Fibrosis
• Long-noncoding RNAs
• M1
• M2
• Macrophages
• MicroRNA
• Non-coding RNA
• Radiation-induced lung fibrosis

• T32 CA154274 NCI NIH HHS

CD4⁺ T cells play an important role in regulating silica-induced inflammation and fibrosis. Recent studies showed that Wnt/β-catenin pathway could modulate the function and the differentiation of CD4⁺ T cells. Therefore, Wnt/β-catenin pathway may participate in the development and progress of silicosis. To investigate the role of Wnt/β-catenin pathway, we used lentivirus expressing β-catenin shRNA to block the Wnt/β-catenin pathway by intratracheal instillation to the mice model of silicosis. Treatment of lentivirus could significantly aggravate the silica-induced lung inflammation and attenuated the fibrosis at the late stage. By analyzing CD4⁺ T cells, we found that blockade of Wnt/β-catenin pathway suppressed regulatory T cells (Tregs). Reciprocally, enhanced Th17 response was responsible for the further accumulation of neutrophils and production of proinflammatory cytokines. In addition, blockade of Wnt/β-catenin pathway delayed the Th1/Th2 polarization by inhibiting Tregs and Th2 response. These results indicated that Wnt/β-catenin pathway could regulate Tregs to modulate Th immune response, which finally altered the pathological character of silicosis. Our study suggested that Wnt/β-catenin pathway might be a potential target to treat the silica-induced inflammation and fibrosis.

• connective tissues disease
• interferon γ
• interleukin 4
• interleukin 9
• interstitial lung disease

T helper 9 (Th9) cells, a recently recognized Th cell subset, are involved in autoimmune diseases. We aimed to investigate the role of Th9/interleukin-9 (IL-9) in the pathogenesis of hepatic fibrosis. Th9 and Th17 cells were quantified in chronic hepatitis B (CHB) patients with hepatic fibrosis, HBV-associated liver cirrhosis (LC) patients and healthy controls (HC). The percentages of Th9 and Th17 cells, concentrations of IL-9 and IL-17, as well as expression of IL-17, TNF-α, IL-6, IL-4, IL-21, TGF-β1 and IFN-γ were significantly increased in plasma of CHB and LC patients compared with those in HC. Splenic Th9 and Th17 cells, plasma concentrations and liver expression of IL-9 and IL-17A were significantly elevated in mice with hepatic fibrosis compared with controls. Neutralization of IL-9 in mice ameliorated hepatic fibrosis, attenuated the activation of hepatic stellate cells, reduced frequencies of Th9, Th17 and Th1 cells in spleen, and suppressed expression of IL-9, IL-17A, IFN-γ, TGF-β1, IL-6, IL-4 and TNF-α in plasma and liver respectively. Our data suggest a deleterious role of Th9/IL-9 in increasing hepatic fibrosis and exacerbating disease endpoints, indicating that Th9/IL9 based immunotherapy may be a promising approach for treating hepatic fibrosis.

• Chemokines
• Cytokines
• Fibrosing disorders
• Fibrosis
• Macrophage polarization
• Macrophages
• Monocytes

• R21 AR061680 NIAMS NIH HHS

• IL-1α
• granuloma
• macrophage proliferation
• particles
• pulmonary alveolar proteinosis

Ge-imogolites are short aluminogermanate tubular nanomaterials with attractive prospected industrial applications. In view of their nano-scale dimensions and high aspect ratio, they should be examined for their potential to cause respiratory toxicity. Here, we evaluated the respiratory biopersistence and lung toxicity of 2 samples of nanometer-long Ge-imogolites.

Rats were intra-tracheally instilled with single wall (SW, 70 nm length) or double wall (DW, 62 nm length) Ge-imogolites (0.02-2 mg/rat), as well as with crocidolite and the hard metal particles WC-Co, as positive controls. The biopersistence of Ge-imogolites and their localization in the lung were assessed by ICP-MS, X-ray fluorescence, absorption spectroscopy and computed micro-tomography. Acute inflammation and genotoxicity (micronuclei in isolated type II pneumocytes) was assessed 3 d post-exposure; chronic inflammation and fibrosis after 2 m.

Cytotoxic and inflammatory responses were shown in bronchoalveolar lavage 3 d after instillation with Ge-imogolites. Sixty days after exposure, a persistent dose-dependent inflammation was still observed. Total lung collagen, reflected by hydroxyproline lung content, was increased after SW and DW Ge-imogolites. Histology revealed lung fibre reorganization and accumulation in granulomas with epithelioid cells and foamy macrophages and thickening of the alveolar walls. Overall, the inflammatory and fibrotic responses induced by SW and DW Ge-imogolites were more severe (on a mass dose basis) than those induced by crocidolite. A persistent fraction of Ge-imogolites (15% of initial dose) was mostly detected as intact structures in rat lungs 2 m after instillation and was localized in fibrotic alveolar areas. In vivo induction of micronuclei was significantly increased 3 d after SW and DW Ge-imogolite instillation at non-inflammatory doses, indicating the contribution of primary genotoxicity.

We showed that nm-long Ge-imogolites persist in the lung and promote genotoxicity, sustained inflammation and fibrosis, indicating that short high aspect ratio nanomaterials should not be considered as innocuous materials. Our data also suggest that Ge-imogolite structure and external surface determine their toxic activity.

The online version of this article (doi:10.1186/s12989-014-0067-z) contains supplementary material, which is available to authorized users.

The cellular mechanisms involved in the development of silicosis have not been fully elucidated. This study aimed to examine influence of silica-induced lung injury on autophagy. Suspensions of crystalline silica particles were administered transnasally to C57BL/6j mice. Immunohistochemical examination for Fas and p62 protein expression was performed using lung tissue specimens. Two-dimensional and quantitative analysis of silica deposits in the lungs were performed in situ using lung tissue sections by an in-air microparticle induced X-ray emission (in-air micro-PIXE) analysis system, which was based on irrradiation of specimens with a proton ion microbeam. Quantitative analysis showed a significant increase of iron levels on silica particles (assessed as the ratio of Fe relative to Si) on day 56 compared with day 7 (p<0.05). Fas and p62 were expressed by histiocytes in granulomas on day 7, and the expressions persisted for day 56. Fas- and p62-expressing histiocytes were co-localized in granulomas with silica particles that showed an increase of iron levels on silica particles in mouse lungs. Iron complexed with silica induces apoptosis, and may lead to dysregulations of autophagy in histiocytes of granulomas, and these mechanisms may contribute to granuloma development and progression in silicosis.

• Fas
• apoptosis
• autophagy
• p62
• silicosis

• Acute Disease
• Animals
• Bronchi/immunology
• Bronchi/physiopathology
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/pathology
• Cytokines/immunology
• Eicosanoids/immunology
• Epithelial Cells/immunology
• Epithelial Cells/pathology
• Fibroblasts/immunology
• Fibroblasts/pathology
• Humans
• Intercellular Signaling Peptides and Proteins/immunology
• Mice
• Pulmonary Alveoli/immunology
• Pulmonary Alveoli/physiopathology
• Pulmonary Fibrosis/immunology
• Pulmonary Fibrosis/pathology
• Pulmonary Fibrosis/physiopathology
• T-Lymphocyte Subsets/immunology
• T-Lymphocyte Subsets/pathology

Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease.

• Animals
• Asthma/immunology
• Asthma/physiopathology
• CD4-Positive T-Lymphocytes/immunology
• Dendritic Cells/immunology
• Epithelial Cells/metabolism
• Humans
• Hypersensitivity/immunology
• NF-kappa B/metabolism
• Nitrogen Dioxide/immunology
• Serum Amyloid A Protein/metabolism
• Severity of Illness Index

• P20 RR021905 NCRR NIH HHS
• P20 RR 021905 NCRR NIH HHS
• R01 HL107291 NHLBI NIH HHS
• R01 HL089177 NHLBI NIH HHS
• P20 GM103496 NIGMS NIH HHS
• P20 RR015557 NCRR NIH HHS
• P20 RR15557 NCRR NIH HHS

• asthma
• epithelium
• dendritic cells
• cd4⁺ t cells
• reactive oxygen species
• reactive nitrogen species
• nf-kappab

• Animals
• Asthma/etiology
• Asthma/metabolism
• CD4-Positive T-Lymphocytes/physiology
• Dendritic Cells/physiology
• Humans
• NF-kappa B/physiology
• Reactive Nitrogen Species/metabolism
• Reactive Oxygen Species/metabolism
• Respiratory Mucosa/physiology