transforming-growth-factor-beta and Lung-Diseases--Obstructive

Asthma and chronic obstructive pulmonary disease are respiratory disorders and a major global health problem with increasing incidence and severity. Genes originally associated with lung development could be relevant in the pathogenesis of chronic obstructive pulmonary disease/asthma, owing to either an early-life origin of adult complex diseases or their dysregulation in adulthood upon exposure to environmental stressors (e.g., smoking). The transforming growth factor (TGF)-β superfamily is conserved through evolution and is involved in a range of biological processes, both during development and in adult tissue homeostasis. TGF-β1 has emerged as an important regulator of lung and immune system development. However, considerable evidence has been presented for a role of many of the other ligands of the TGF-β superfamily in lung pathology, including activins, bone morphogenetic proteins, and growth differentiation factors. In this review, we summarize the current knowledge on the mechanisms by which activin, bone morphogenetic protein, and growth differentiation factor signaling contribute to the pathogenesis of obstructive airway diseases.

Topics: Activins; Animals; Bone Morphogenetic Proteins; Humans; Lung; Lung Diseases, Obstructive; Transforming Growth Factor beta

COPD is characterized by chronic inflammation and injury of both the airways and the parenchymal structures of the lung. These processes are associated with ongoing repair. Whether repair leads to restoration of normal tissue architecture or to altered tissue structure with loss of function depends on complex interrelationships of a variety of interacting mediators. The possibility that repair processes can be modulated by exogenous agents raises the possibility that therapeutic strategies aimed at repair can be effective. Such strategies offer tremendous promise both for slowing the relentlessly progressive natural history which most often characterizes COPD and, possibly, for restoring lung function. Rennard SI. Inflammation and repair processes in chronic obstructive pulmonary disease.

Topics: Animals; Bronchitis; Cell Division; Cell Movement; Fibronectins; Humans; Lung Diseases, Obstructive; Pneumonia; Respiratory Mucosa; Transforming Growth Factor beta; Wound Healing

Transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8), and leukotrienes are potent neutrophil chemoattractants that are released in several lung diseases. There is limited information about the release of TGF-beta in bronchoalveolar lavage fluid (BALF) of patients with pneumonia. Furthermore, it is not clear if TGF-beta is differentially expressed in different lung diseases. The aim of our study was to compare the concentrations of TGF-beta1 and TGF-beta2 in the BALF of patients with pneumonia and other lung diseases. Furthermore, correlation of the TGF-beta levels with the concentration of chemoattractant mediators as well as with indicators of macrophage and granulocyte activation should be investigated. Patients with pneumonia, interstitial lung disease (ILD), or chronic obstructive pulmonary diseases (COPD) were included. Patients with ischemic heart disease without pulmonary involvement served as controls. The concentrations of TGF-beta1 and TGF-beta2, of the chemoattractant cytokine IL-8, of leukotriene B4, and of the leukotrienes C4, D4, and E4 were measured. Neutrophil elastase and granulocyte content (PMN) were used as markers for granulocyte activation, and neopterin was used as a marker for the activation of macrophages. Significantly elevated levels of TGF-beta1 (mean = 0.216 ng/ml, p < 0.01) were found in patients with microbiologically positive pneumonia but not in patients with ILD or COPD. A significant (p < 0.001) correlation was found between the TGF-beta1 concentrations and the IL-8 levels and the percentage of granulocytes (r = 0.76, and r = 0.44, respectively). Elevated TGF-beta2 concentrations were measured in the BALF of patients with pneumonia (mean = 1.4 ng/ml, p < 0.01) and with ILD. Pneumonia was also associated with increased concentrations of leukotrienes C4, D4, and E4 (mean = 91.61 pg/ml, p < 0.05) and leukotriene B4 (mean = 203.9 pg/ml, p < 0.01), significantly elevated levels of PMN elastase (mean = 2958.26 ng/ml, p < 0.01), and neopterin (mean = 0.42 nmol/L). Our results strongly suggest that different lung diseases do differ with regard to the released cytokines. TGF-beta1 probably plays a key role in regulation of pulmonary inflammation, particularly in pneumonia.

Topics: Bronchoalveolar Lavage Fluid; Granulocytes; Humans; Interleukin-8; Leukocyte Elastase; Leukotrienes; Lung Diseases, Interstitial; Lung Diseases, Obstructive; Macrophages; Monocytes; Neopterin; Pneumonia; Transforming Growth Factor beta

Airway remodeling may play an important role in heaves pathophysiology. Transforming growth factor-beta 1 (TGF-beta1) is a potent profibrotic cytokine, which might contribute to airway wall thickening and fibrosis of bronchiolar and alveolar submucosa. An ELISA designed for the measurement of human TGF-beta1 was used to measured total TGF-beta1 released in bronchoalveolar lavage fluid (BALF) of normal horses and of those affected with heaves in remission. The specificity of the assay for TGF-beta1 of the horse was confirmed using recombinant equine TGF-beta1. The influence of hay exposure on TGF-beta1 release in the airways was also examined by stabling horses in a dusty environment. TGF-beta1 was found in the BALF of all horses. However, no significant difference between basal concentration of TGF-beta1 in BALF of control horses versus that of horses affected with heaves was found. Furthermore, no differences were identified in these populations 1 and 9 days after allergen challenge. In conclusion, these data indicate that TGF-beta1 is released in BALF fluid of horses in biologically active concentrations. Other studies are necessary for a better definition of the role of this cytokine within the lung, as our study does not establish a causal relationship between TGF-beta1 and the pathophysiology of heaves in the horse.

Topics: Allergens; Animals; Bronchoalveolar Lavage Fluid; CHO Cells; Cricetinae; Dust; Enzyme-Linked Immunosorbent Assay; Horse Diseases; Horses; Lung Diseases, Obstructive; Recombinant Proteins; Respiratory Function Tests; Transforming Growth Factor beta

Tobacco smoke is believed to cause small airway disease and then chronic obstructive pulmonary disease (COPD), but the molecular mechanisms by which small airway obstruction occurs remain unknown. To study the gene expression levels of transforming growth factor (TGF)-beta1, a potent fibrogenic factor, in small airway epithelium from smokers and patients with COPD, we harvested highly pure samples of epithelial cells from small airways under direct vision by using an ultrathin bronchofiberscope BF-2.7T (outer diameter 2.7 mm with a biopsy channel of 0.8 mm in diameter). The expression levels of TGF-beta1 were evaluated by reverse transcription-polymerase chain reaction (RT-PCR). The mRNA levels of TGF-beta1 corrected by beta-actin transcripts were significantly higher in the smoking group and patients with COPD than those in nonsmokers (p < 0.01). Furthermore, among smokers and patients with COPD, TGF-beta1 mRNA levels correlated positively with the extent of smoking history (pack-years) and the degree of small airway obstruction as assessed by measurements of flow-volume curves. Immunocytochemistry of the cells demonstrated more intense stainings for TGF-beta1 in samples from smokers and patients with COPD than from nonsmokers. Spontaneously released immunoreactive TGF-beta1 levels from cultured epithelial cells were more elevated in subjects with a history of smoking and patients with COPD than in nonsmokers. Our study showed a close link between smoking and expression of TGF-beta1 in small airways. Our results also suggested that small airway epithelial cells might be involved in obstructive changes found in smokers and patients with COPD.

Topics: Analysis of Variance; Biopsy; Bronchi; Bronchoscopy; Case-Control Studies; Cells, Cultured; Female; Forced Expiratory Volume; Gene Expression Regulation; Humans; Immunohistochemistry; Lung Diseases, Obstructive; Male; Middle Aged; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Smoking; Transforming Growth Factor beta; Vital Capacity

Chronic airways inflammation is one of the features of chronic obstructive pulmonary disease (COPD). We demonstrated previously that bronchiolar epithelium in COPD contains increased numbers of macrophages and mast cells. Transforming growth factor beta1 (TGF-beta1) may be involved in this influx because it has chemotactic activity for macrophages and mast cells. In this study, we examined expression patterns of TGF-beta1, TGF-beta receptors type I and II (TGF-betaRI and TGF-betaRII) by immunohistochemistry and mRNA in situ hybridization in peripheral lung tissue of 14 current or ex-smokers with COPD (FEV1 < 75%) and 14 without COPD (FEV1 > 84%). In both groups, TGF-beta1 and its receptors are present in airway and alveolar epithelial cells, airway and vascular smooth muscle cells, and tissue and alveolar CD68(+) cells (considered herein to be macrophages). In subjects with COPD, a semiquantitative analysis revealed approximately twofold higher levels of TGF-beta1 mRNA and protein in bronchiolar and alveolar epithelium (p < 0.02) as compared with subjects without COPD. With regard to bronchiolar epithelial cells, we found a significant correlation between TGF-beta1 mRNA and protein expression (r = 0.62; p < 0.002), and between the FEV1 of all subjects together and TGF-beta1 protein (r = -0.60; p < 0.0002) and mRNA (r = -0.67; p < 0. 002) levels. The epithelial expression of TGF-beta1 mRNA and TGF-beta1 protein correlates with the number of intraepithelial macrophages (both: r = 0.44; p < 0.03) whereas intraepithelial mast cell numbers correlate with epithelial TGF-beta1 mRNA expression. These data suggest a role for TGF-beta1 in recruiting macrophages into the airway epithelium in COPD.

Topics: Adult; Aged; Bronchi; Cell Count; Chemotaxis; Epithelial Cells; Epithelium; Female; Forced Expiratory Volume; Gene Expression Regulation; Humans; Immunohistochemistry; In Situ Hybridization; Lung Diseases, Obstructive; Macrophages; Macrophages, Alveolar; Male; Mast Cells; Middle Aged; Muscle, Smooth, Vascular; Pulmonary Alveoli; Receptors, Transforming Growth Factor beta; RNA, Messenger; Smoking; Transforming Growth Factor beta

Asthmatic airways have a characteristic deposition of connective tissue under the epithelial basement membrane, but the mediators involved in this alteration are unknown. Several authors have postulated that transforming growth factor beta 1 (TGF-beta 1) could be overexpressed in asthmatic airways.. Lung samples from 16 asthmatic patients, six patients with chronic obstructive pulmonary disease (COPD), and six non-obstructed smokers were analysed. RNA was extracted from these tissues to measure expression of TGF-beta 1 by Northern blot analysis using a cDNA probe for TGF-beta 1. The level of expression was quantitated by densitometry using glyceraldehyde 3-phosphate dehydrogenase mRNA as a control. TGF-beta 1 was localised to specific cell types in these lungs by immunohistochemical analysis using polyclonal antibodies specific for intracellular and extracellular TGF-beta 1.. The 2.5 kb TGF-beta 1 mRNA was seen in all 18 samples analysed by Northern blotting and densitometric analysis showed no difference between the asthmatic group (mean (SD) 108% (43%)), the group with COPD (122% (33%)), and the non-obstructed group (100% (49%)). The TGF-beta 1 precursor was immunolocalised throughout the airway wall including the epithelium and in alveolar macrophages. The mature TGF-beta 1 was localised primarily within the connective tissue of the airway wall. These patterns of expression of both forms of TGF-beta 1 were similar in lungs from asthmatic patients, those with COPD, and controls.. While TGF-beta 1 mRNA and protein are abundantly expressed in human lungs, there is no clear difference in expression between the airways of asthmatic subjects and those of smokers with and without COPD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Blotting, Northern; Child; Child, Preschool; DNA Probes; Female; Gene Expression; Humans; Immunohistochemistry; Lung; Lung Diseases, Obstructive; Male; Middle Aged; RNA, Messenger; Smoking; Transforming Growth Factor beta