transforming-growth-factor-beta and Sarcoidosis--Pulmonary

Alveolitis and the production of proinflammatory cytokines are known features of sarcoidosis. Because of the usually spontaneous resolution of alveolitis despite local secretion of mediators causing inflammation and granuloma formation, we hypothesized that downmodulating mechanisms such as anti-inflammatory cytokines might be involved in this process.. Investigation of the secretion of the macrophage deactivating cytokines interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) by alveolar macrophages in untreated sarcoidosis of the lung.. Fourteen consecutive and untreated patients with pulmonary sarcoidosis and 18 volunteers underwent bronchoscopy. Alveolar macrophages (AM) were obtained by bronchoalveolar lavage and the secretion of IL-10 and TGF-beta was studied.. Spontaneous IL-10 production by AM was found in 6 of 14 patients and in 2 of 18 controls. The IL-10 level of lipopolysaccharide-stimulated AM was significantly higher in patients. Monocytes secreted significantly more IL-10 than AM, but there was no difference between sarcoid and control monocytes. No difference was found in the secretion of TGF-beta between patients and controls.. Increased local secretion of IL-10 - but not TGF-beta - may represent a downmodulating mechanism involved in the spontaneous resolution of alveolitis in sarcoidosis.

Topics: Adult; Bronchoalveolar Lavage Fluid; Bronchoscopy; Down-Regulation; Female; Humans; Interleukin-10; Macrophages, Alveolar; Male; Middle Aged; Monocytes; Probability; Reference Values; Sarcoidosis, Pulmonary; Severity of Illness Index; Statistics, Nonparametric; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) is a cytokine that promotes extracellular matrix accumulation and inhibits matrix degradation. Although the natural course of sarcoidosis is usually favourable, granuloma healing in the lung may result in pulmonary fibrosis and respiratory impairment in some patients. In this study TGF-beta1 was evaluated in bronchoalveolar lavage (BAL) fluid and culture supernatants of alveolar macrophages (AM) from 73 patients with biopsy-proven sarcoidosis. Disease activity was defined when patients recently developed or increased symptoms (cough, dyspnoea, systemic symptoms) and/or demonstrated increasing opacities on chest radiography. Pulmonary function tests were performed in all patients including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and the diffusing capacity of the lung for carbon monoxide (DL,CO). Fourteen patients with idiopathic pulmonary fibrosis (IPF) and 14 healthy subjects were investigated as a control group. Immunohistochemistry was used to evaluate the cell distribution of TGF-beta1 on lung specimens. TGF-beta1 levels in BAL and in AM supernatants were not different between sarcoidosis and healthy subjects, whereas they were markedly increased in IPF. However, the TGF-beta1 level was significantly increased in BAL fluid but not in AM supernatants from sarcoidosis with altered lung function, compared with patients with normal lung function. The TGF-beta1 level in BAL was increased in active sarcoidosis but this increased level was mainly related to the higher level observed in patients with altered lung function. TGF-beta1 levels in BAL correlated significantly with the lymphocyte percentage. TGF-beta1 staining assessed by immunohistochemistry was intense in epithelioid histiocytes comprising non-necrotizing granuloma and in bronchiolar epithelial cells, in hyperplastic type II pneumocytes and occasionally in AM. This study supports the hypothesis that overproduction of transforming growth factor-beta1 is associated with functional impairment in patients with pulmonary sarcoidosis.

Topics: Adult; Analysis of Variance; Biopsy, Needle; Bronchoalveolar Lavage Fluid; Cells, Cultured; Female; Humans; Immunohistochemistry; Logistic Models; Macrophages, Alveolar; Male; Middle Aged; Prospective Studies; Pulmonary Fibrosis; Reference Values; Respiratory Function Tests; Sarcoidosis, Pulmonary; Transforming Growth Factor beta

Sarcoidosis is a systemic, granulomatous disorder with a high rate of spontaneous remission indicating the presence of antiinflammatory mechanisms. Antiinflammatory mediators such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) should be able to induce spontaneous remission of sarcoidosis. By measuring the release of both mediators in culture supernatants of bronchoalveolar lavage (BAL) cells, we investigated their relevance in the spontaneous remission of sarcoidosis. No spontaneous IL-10 release was observed by BAL cells of sarcoid patients. In supernatants of BAL cells of seven patients found retrospectively to be free of any interstitial lung disease, we found 612 +/- 261.2 pg/ml (mean +/- SEM) TGF-beta. TGF-beta release was recorded in 20 of 39 patients with active disease. Patients with active disease without TGF-beta release in BAL cell culture either required therapy (n = 21; 677 +/- 159 pg/ml) or showed evidence of persisting disease (n = 6; 762 +/- 419 pg/ml). Patients with active disease without indications for therapy and with significantly increased TGF-beta release (n = 12; 1,422 +/- 215 pg/ml; p < 0.004 in all comparisons) had a spontaneous remission within 6 mo. Increased TGF-beta release (1,560 +/- 353 pg/ml) was observed in five of five patients receiving therapy. We conclude that TGF-beta is a regulator of the inflammatory process in sarcoidosis.

Topics: Adrenal Cortex Hormones; Adult; Bronchoalveolar Lavage Fluid; Cells, Cultured; Humans; Interleukin-10; Middle Aged; Pulmonary Alveoli; Remission, Spontaneous; Sarcoidosis, Pulmonary; Transforming Growth Factor beta

Sarcoidosis is a multisystemic granulomatous inflammation associated with Th17/regulatory T cell (Treg) polarization. As a marker of inflammation, serum amyloid A (SAA) could upregulate the expression of chemokine ligand 20 (CCL20), which induces the migration of Treg cells and Th17 cells by binding and activating thechemokine C-C receptor (CCR) 6. Our goal was to determine whether SAA/anti-CCL20 induces Th17/Treg rebalance in pulmonary sarcoidosis. The deposition of SAA- and Th17/Treg-related proteins in SodA-induced granulomas was tested using immunohistochemistry. Mice with SodA-induced sarcoidosis were treated with SAA or SAA + anti-CCL20, and then Th1/Th2 and Th17/Treg cells were detected by fluorescence-activated cell sorting (FACS) analysis. The expression of SAA/CCL20 and IL-23/IL-17A was detected by enzyme-linked immunosorbent assay (ELISA) and multiplex. Key proteins in the TGF-β/Smad signaling pathway were tested by western blot. SAA mainly plays a pro-inflammatory role by promoting the expression of CCL20 and IL-17A in bronchoalveolar lavage fluid (BALF) and serum, exacerbating this elevation of CD4+/CD8+ T cells in both mediastinal lymph nodes (LNs) and BALF, as well as proliferating Th1 in LNs in SodA-induced pulmonary sarcoidosis. In addition, SAA could also promote the proliferation of Tregs in LNs. Intriguingly, blocking of CCL20 could partially reverse the expression of Th17-related cytokine, ameliorate Th1/Th2 and Treg/Th17 bias in mice with SodA-induced pulmonary sarcoidosis, and rescue the overactivation of the TGF-β/Smad2/Smad3 signaling pathway. Anti-CCL20 may have the potential for therapeutic translation, targeting on the immunopathogenesis of pulmonary sarcoidosis.

Topics: Animals; Chemokines; Inflammation; Interleukin-17; Ligands; Mice; Sarcoidosis; Sarcoidosis, Pulmonary; Serum Amyloid A Protein; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Sarcoidosis is a systemic inflammatory granulomatous disease, frequently affecting the lung. If left untreated, it may end in lung fibrosis. Proangiogenic and profibrotic vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, fibroblast growth factor (FGF)-2 and platelet-derived growth factor (PDGF)-AB are a known therapeutical target in pulmonary fibrosing diseases, e.g. IPF, but there is no targeted therapy option for pulmonary fibrosis in sarcoidosis.. The aim of our study was to determine the association of these markers' serum levels on lung function and the patients' quality of life in a long-term follow-up of sarcoidosis patients, to provide further information for finding targeted therapy options for pulmonary sarcoidosis.. 54 patients with sarcoidosis underwent blood sampling, pulmonary function testing and answered the King's Brief Interstitial Lung Disease (K-BILD) questionnaire at baseline and at three-years follow-up. Serum levels of profibrotic and angiogenic markers were assessed at baseline by enzyme-linked immunosorbent assay.. Between 2015 and 2018, 54 patients with biopsy proven sarcoidosis were enrolled. Throughout the observation period, there was a significant decrease in the diffusion capacity for carbon monoxide (DLCO) [%] (-6.5504 ± 13,39, p = 0.001) and forced expiratory volume in one second predicted (FEV1) [%] (-6.07 ± 12.09, p = 0.001). Patients with greater impairment of forced vital capacity (FVC) did have significantly higher serum levels of VEGF (p = 0.03) and PDGF-AB (p<0.001). The K-BILD questionnaire did not change significantly during follow-up. However, patients with worsening K-BILD scores did have significantly higher serum-levels of PDGF-AB (2.67 pg/ml ± 0.93 vs. 1.88 pg/ml ± 0.60, p = 0.004) at baseline, compared to those with unchanged or increasing K-BILD scores.. Among patients with pulmonary sarcoidosis, baseline serum levels of VEGF and PDGF-AB were associated with pulmonary function impairment. Furthermore, PDGF-AB was associated with worsening K-BILD scores. No such association was observed for FGF-2 and TGF-ß1. VEGF and PDGF-AB may be possible prognostic and therapeutic targets in sarcoidosis as a fibrosing ILD beyond IPF.

Topics: Adult; Aged; Biomarkers; Female; Fibroblast Growth Factor 2; Fibrosis; Humans; Lung; Male; Middle Aged; Platelet-Derived Growth Factor; Quality of Life; Sarcoidosis, Pulmonary; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Pulmonary sarcoidosis (PS) is a noncaseating granulomatous disease of unknown origin. Despite conflicting reports, it is considered that the regulatory T (Treg) cells are functionally impaired in PS, but the underlying mechanisms remain unclear. OX40, a pivotal costimulatory molecule, is essential for T-cell functions and memory development, but its impact on Treg cells is ambiguous.. Does the OX40 pathway influence the suppressive functions of Treg cells in PS?. Fifty treatment-naïve patients with PS and 30 healthy control participants were recruited for this study. Polychromatic flow cytometry-based immunologic assays were performed to enumerate effector T helper (Th) cells and Treg cells along with their functions. Using real-time polymerase chain reaction analysis, small interfering RNA, and pharmacologic inhibitors, the impact of OX40 on Treg cell function was investigated.. We observed enrichment of Th-9 cells perhaps for the first time along with Th-1, Th-17, and Treg cells in patients' BAL fluid (BALF) compared with peripheral blood. However, Treg cells were observed to be functionally defective at the pathological site. We observed higher expression of OX40 on both T effector (CD4. We propose that inhibiting the OX40 pathway may constitute a therapeutic strategy for controlling inflammatory T cells by restoring Treg cell functions in patients with PS.

Topics: Adult; Bronchoalveolar Lavage Fluid; Cross-Sectional Studies; Drug Discovery; Female; Humans; Immunologic Memory; Immunologic Tests; Inflammation; Interferon-gamma; Interleukin-10; Male; Receptors, OX40; Sarcoidosis, Pulmonary; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The feature of pulmonary sarcoidosis is characterized by a Th1/Th17/regulatory T cells (Tregs) -driven inflammatory process in lung, resulting in noncaseating granulomas containing CD4+ T cells. Tregs increase in both lung and peripheral blood, with damaged immunoregulatory function. The current study investigated the effects of IL33 or anti-IL23 antibody on restoring the homeostasis and functions of Tregs in mycobacterial superoxide dismutase A (SodA)-induced pulmonary sarcoidosis. IL33 or anti-IL23 antibody was administered to mice with late-stage pulmonary sarcoidosis. The levels of Th1/Th17/Tregs and Tregs' suppressive functions were detected by fluorescence activated cell sorting (FACS) analysis or qPCR. The expressions of key proteins in PI3K/Akt/mTOR and TGF-β/Smad2/Smad3 signaling pathways were tested by western blot. IL33 administration was associated with the rebalance of Th1/Th2 and Tregs, as well as a superior suppressor activity of Tregs on effector T cells in sarcoidosis, probably through increasing ST2 expressions on Tregs, along with the suppression of PI3K/Akt/mTOR and TGF-β/Smad2/Smad3 signaling pathways. Small dose of anti-IL23 antibody independently improved Th1/Th2 bias, but had limited effects on the homeostasis and ST2 expressions on Tregs. These results suggested a major anti-inflammatory ability of IL33 to ameliorate the disturbance of Th1/Th2 and Tregs in pulmonary sarcoidosis, and provided rationales for further strategies of targeting the IL33/ST2 signals in the treatment of pulmonary sarcoidosis.

Topics: Animals; Female; Interleukin-23; Interleukin-33; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Sarcoidosis, Pulmonary; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Transforming Growth Factor beta

Lung fibrosis is a complication of sarcoidosis, in which TGF-β/Smad pathway may play an important role. We evaluated gene expression of TGF-β1, SMAD2, 3 and 7 in bronchoalveolar lavage (BAL) cells and peripheral blood (PB) lymphocytes of sarcoidosis patients (n=94) to better understand the mechanisms of sarcoid inflammation. The relative gene expression was analyzed by qPCR method. Selected clinical/radiological features and biochemical markers were taken into account in the analysis. We found that TGF-β1 and SMAD3 expressions in PB lymphocytes were significantly higher in sarcoidosis patients. Up-regulation of SMAD7 (inhibitory Smad) and down-regulation of SMAD3 in BAL cells in all subgroups were found. The expression of TGF-β1 in PB lymphocytes was the highest in patients with lung parenchymal involvement and in the insidious onset phenotype. The expression of TGF-β1 in BAL cells was higher in patients with abnormal spirometry (p=0.012), and TGF-β1 and SMAD3 in patients with restrictive pattern (p=0.034 and 0.031, respectively). Several statistically significant negative correlations were found between the expression levels of SMAD2 and 3 in BAL cells and various LFT parameters. We conclude that TGF-β/Smad pathway is involved in the pathogenesis of pulmonary sarcoidosis. These biomarkers (especially TGF-β1, SMAD2 and 3) are of a negative prognostic value.

Topics: Adult; Biomarkers; Bronchoalveolar Lavage Fluid; Female; Gene Expression; Humans; Lymphocytes; Male; Middle Aged; Prognosis; RNA, Messenger; Sarcoidosis, Pulmonary; Smad Proteins; Smad2 Protein; Smad3 Protein; Smad7 Protein; Transforming Growth Factor beta

The chronic course of pulmonary sarcoidosis can lead to lung dysfunction due to fibrosis, in which the signalling pathways TGF-β/Smad and VEGF-A may play a key role.. We evaluated immunoexpression of TGF-β1, Smad2, 3, and 7, and VEGF-A in serum and bronchoalveolar lavage (BAL) fluid of patients (n = 57) classified according to the presence of lung parenchymal involvement (radiological stage I vs. II-III), acute vs. insidious onset, lung function test (LFT) results, calcium metabolism parameters, percentage of BAL lymphocytes (BAL-L%), BAL CD4(+)/CD8(+) ratio, age, and gender. Immunoexpression analysis of proteins was performed by ELISA.. The immunoexpression of all studied proteins were higher in serum than in BAL fluid of patients (p >0.05). The serum levels of TGF-β1 (p = 0.03), Smad2 (p = 0.01), and VEGF-A (p = 0.0002) were significantly higher in sarcoidosis patients compared to healthy controls. There were no differences within the sarcoidosis group between patients with vs. without parenchymal involvement, acute vs. insidious onset, or patients with normal vs. abnormal spirometry results. In patients with abnormal spirometry results a negative correlation was found between forced vital capacity (FVC) % predicted value and TGF-β1 immunoexpression in BAL fluid, and positive correlations were observed between the intensity of lung parenchymal changes estimated by high-resolution computed tomography (HRCT scores) and Smad 2 level in serum.. TGF-β/Smad signalling pathway and VEGF-A participate in the pathogenesis of sarcoidosis. BAL TGF-β1, and Smad 2 in serum seem to be promising biomarkers with negative prognostic value, but further studies are required to confirmed our observations.

Topics: Adult; Biomarkers; Bronchoalveolar Lavage Fluid; Case-Control Studies; Female; Humans; Male; Phenotype; Respiratory Function Tests; Sarcoidosis, Pulmonary; Smad Proteins; Tomography, X-Ray Computed; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Recent studies show that various inflammatory diseases are regulated at the level of RNA translation by small non-coding RNAs, termed microRNAs (miRNAs). We sought to determine whether sarcoidosis tissues harbor a distinct pattern of miRNA expression and then considered their potential molecular targets.. Genome-wide microarray analysis of miRNA expression in lung tissue and peripheral blood mononuclear cells (PBMCs) was performed and differentially expressed (DE)-miRNAs were then validated by real-time PCR. A distinct pattern of DE-miRNA expression was identified in both lung tissue and PBMCs of sarcoidosis patients. A subgroup of DE-miRNAs common to lung and lymph node tissues were predicted to target transforming growth factor (TGFβ)-regulated pathways. Likewise, the DE-miRNAs identified in PBMCs of sarcoidosis patients were predicted to target the TGFβ-regulated "wingless and integrase-1" (WNT) pathway.. This study is the first to profile miRNAs in sarcoidosis tissues and to consider their possible roles in disease pathogenesis. Our results suggest that miRNA regulate TGFβ and related WNT pathways in sarcoidosis tissues, pathways previously incriminated in the pathogenesis of sarcoidosis.

Topics: Gene Expression; Gene Expression Profiling; Humans; Integrases; Lung; Lymph Nodes; MicroRNAs; Molecular Targeted Therapy; Sarcoidosis, Pulmonary; Transforming Growth Factor beta; Wnt Proteins

Pulmonary sarcoidosis has a variable course ranging from self-limiting disease to progressive fibrosis. Activation of fibroblasts, myofibroblast transformation, and matrix production may contribute to pulmonary damage in sarcoidosis. These processes are influenced by pulmonary cytokines which can be measured in bronchoalveolar lavage fluid (BALF). In order to clarify the incompletely understood fibrotic process in sarcoidosis, we classified activity of sarcoidosis according to WASOG criteria, measured TNF-α, IL-6, and HGF in BALF, and assessed the effect of HGF and BALF on proliferation and matrix production of human lung fibroblasts.. BALF was obtained from 34 consecutive patients with sarcoidosis. BALF of active sarcoidosis contained elevated levels of TNF-α, HGF, and IL-6 and stimulated fibroblast proliferation. BALF of inactive sarcoidosis, but not of active sarcoidosis, stimulated the production of matrix proteins. HGF levels in inactive sarcoidosis were below those of control patients. HGF suppressed TGF-β-induced matrix expression and transformation of fibroblasts into myofibroblasts.. Prevention of TGF-β-induced myofibroblast transformation may account for the inhibitory effect of HGF on matrix production. The strong fibrogenic effect of BALF of inactive sarcoidosis corresponds to the worse clinical course of inactive sarcoidosis compared with active disease and may be related to a lack of protective HGF.

Topics: Actins; Adult; Albumins; Bronchoalveolar Lavage Fluid; Cell Proliferation; Cell Transdifferentiation; Cells, Cultured; Collagen; Collagen Type I; Collagen Type III; Female; Fibroblasts; Fibronectins; Fibrosis; Hepatocyte Growth Factor; Humans; Interleukin-6; Lung; Male; Middle Aged; Sarcoidosis, Pulmonary; Severity of Illness Index; Statistics, Nonparametric; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Pulmonary fibrosis develops in approximately 25% of patients with chronic sarcoidosis. Transforming growth factor (TGF)-beta1 plays a central role in fibrosis, and accruing reports address the implication of TGF-beta2 and TGF-beta3 in this process. We determined whether single-nucleotide polymorphisms (SNPs) in the TGF-beta1, TGF-beta2, and TGF-beta3 genes might contribute to pulmonary fibrosis in sarcoidosis patients.. A hospital in the Netherlands.. Five SNPs per TGF-beta gene were investigated.. Patients with either acute/self-remitting sarcoidosis (n = 50) and Löfgren syndrome (n = 46) or chronic disease with fibrosis (n = 24) and without fibrosis (n = 34) were assessed over a 4-year follow-up period. The control subjects included 315 individuals.. Polymorphism frequencies were not discordant between the patients and control subjects. The TGF-beta3 4875 A allele was significantly higher in fibrotic patients (carrier frequency, 0.29) than in patients with acute/self-remitting (0.06) and chronic (0.03) sarcoidosis combined (corrected p = 0.01; odds ratio [OR], 7.9). The TGF-beta3 17369 C allele carrier frequency was significantly higher in fibrotic patients (0.29) compared to acute/self-remitting (0.08) and chronic (0.06) patients combined (corrected p = 0.05; OR, 5.1). Although not significant after correction, the TGF-beta3 15101 G allele carrier frequency was lower in fibrotic patients (0.79) compared to acute/self-remitting (0.94) and chronic (1.00) patients combined (p = 0.02; corrected p = 0.1; OR, 0.15). The TGF-beta2 59941 G allele was more abundant in fibrotic patients (carrier frequency, 0.62) compared to patients with acute/self-remitting (0.41) and chronic sarcoidosis combined (0.28) [p = 0.04; corrected p = 0.2; OR, 2.9]. TGF-beta1 gene polymorphisms were not associated with fibrosis.. This study is the first to suggest the implication of genetic variation of TGF-beta3 in the predilection for pulmonary fibrosis developing in sarcoidosis patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Female; Follow-Up Studies; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Pulmonary Fibrosis; Radiography; Sarcoidosis, Pulmonary; Transforming Growth Factor beta

The development of BAL in children for both research and clinical purposes has been limited so far by the difficulty in establishing reference values. The aim of the study was (1) to define composition of BAL cellular components in control children and to evaluate the ability of these cells to express various cytokines, and (2) to study modifications of differential cytology and BAL cell cytokine responses in children with interstitial lung disorders.. Two groups were investigated: a control group of 16 children who were concluded to be free of parenchymal lung disease after complete pulmonary investigation, and a group of 11 children with pulmonary sarcoidosis. Differential cytology was evaluated by standard techniques. BAL cell cytokine expression was studied at the level of messenger RNA (mRNA) by reverse transcription-polymerase chain reaction (RT-PCR) methods.. In the control group, differential cell counts appeared to be similar to values reported in adult populations with normal distribution of the data and no influence of age. In this group, no transcripts for interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and transforming (correction of tranforming) growth factor-beta (TGF-beta) could be detected. In children with sarcoidosis, different profiles of IL-1beta, TNF-alpha, IL-6, and TGF-beta expression were individualized which seemed to be related to the activity and/or severity of the disease, IL-6 and TGF-beta mRNA being observed only in the more severe forms.. These data provide information on BAL cell number and function in children. Characterization of BAL cytokine expression patterns during the course of interstitial lung diseases in children may be of great interest for evaluation of disease activity and/or severity and therefore for planning of therapy.

Topics: Actins; Adolescent; Base Sequence; Blotting, Southern; Bronchoalveolar Lavage Fluid; Cell Count; Child; Child, Preschool; Cytokines; Female; Humans; Interleukin-1; Lung Compliance; Male; Molecular Sequence Data; Polymerase Chain Reaction; Pulmonary Diffusing Capacity; RNA, Messenger; Sarcoidosis, Pulmonary; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Aberrant deposition of extracellular matrices (ECMs) may affect lung inflammation by influencing cell adhesion, migration, and activation. Little is known about the expression of ECMs in lungs with granulomatous inflammation. Therefore the authors investigated the distribution of ECMs, matrix receptors of the integrin family, and transforming growth factor-beta 1 (TGF-beta 1) in lungs from patients with pulmonary sarcoidosis and animals with experimental granulomatosis. Immunohistochemistry revealed increased deposition of type I collagen and fibronectin in human lung granulomas when compared with healthy human lungs. Procollagen type I and cellular fibronectin also were increased, suggesting local synthesis of ECM in sarcoid granulomas. These findings were accompanied by increased staining for fibronectin (alpha 5 beta 1) and collagen (alpha 2 beta 1) integrin receptors. The matrix-inducing cytokine TGF-beta 1 was co-distributed with the aforementioned molecules in the granulomas, whereas no significant staining for TGF-beta 1 was found in healthy lungs. Similar to sarcoid lungs, analysis of lung sections obtained from a murine model of granuloma formation revealed increased expression of fibronectin, collagen, integrin receptors, and TGF-beta 1 within granulomas. Based on these observations, there is increased expression of ECM and matrix receptors in both human and experimental lung granulomas. Such alterations may influence the recruitment and activation of inflammatory cells and fibroblasts, promoting granuloma formation and remodeling of tissue by fibrosis. Activation of mononuclear cells resulting in production of TGF-beta 1 is likely to contribute to the changes described.

Topics: Animals; Collagen; Extracellular Matrix; Fibronectins; Granuloma; Humans; Integrins; Lung Diseases; Mice; Receptors, Cell Surface; Sarcoidosis, Pulmonary; Transforming Growth Factor beta; Trehalose

Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by the formation of nonnecrotizing granulomas in affected tissues, most notably the lungs. Granuloma healing may result in pulmonary fibrosis and respiratory impairment in some patients. Transforming growth factor-beta 1 (TGF-beta 1) is a potent cytokine that promotes fibrosis by enhancing the synthesis of extracellular matrix components, including fibronectin and the alpha 5 beta 1 fibronectin receptor. The role of TGF-beta 1 in promoting lung fibrosis in the setting of pulmonary sarcoidosis has not yet been investigated. Accordingly, we determined the extent and distribution of TGF-beta 1 in lung tissue obtained from seven patients with clinical and histologic features of pulmonary sarcoidosis. The tissue distributions of TGF-beta 1, the TGF-beta 1 binding proteoglycan decorin, fibronectin, and the alpha 5 beta 1 fibronectin receptor were assessed immunohistochemically. In all cases, the epithelioid histiocytes comprising nonnecrotizing granulomas of pulmonary sarcoidosis contained abundant TGF-beta 1. We further demonstrated decorin, fibronectin, and the alpha 5 beta 1 fibronectin receptor within nonnecrotizing granulomas and in the fibrous tissue surrounding the lesions. TGF-beta 1 staining was also observed in bronchiolar epithelial cells, hyperplastic Type II pneumocytes, and occasional alveolar macrophages. This study demonstrates enhanced tissue localization of TGF-beta 1 and related extracellular matrix proteins associated with the nonnecrotizing granulomas of pulmonary sarcoidosis. Through its actions on matrix protein synthesis, TGF-beta 1 may modulate the fibrotic repair process accompanying granuloma healing in sarcoidosis.

Topics: Adult; Aged; Bronchi; Decorin; Epithelioid Cells; Epithelium; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Histiocytes; Humans; Immunohistochemistry; Macrophages, Alveolar; Middle Aged; Proteoglycans; Pulmonary Fibrosis; Radiography; Receptors, Fibronectin; Sarcoidosis, Pulmonary; Severity of Illness Index; Transforming Growth Factor beta; Wound Healing