Biochemical evidence for an increased and progressive deposition of collagen in lungs of patients with pulmonary fibrosis

Abstract

To assess the role of changes in lung collagen in pulmonary fibrosis, the content of this protein was measured in biopsy and autopsy lung from patients with cryptogenic fibrosing alveolitis (CFA), a fibrotic lung disorder of unknown cause. The collagen concentration was measured in lung samples from 21 patients with CFA (14 autopsy and seven open-lung biopsy) and 17 normal subjects; total lung collagen was determined in the right lung of 10 patients who died from CFA and the results were compared with those from 10 normal lungs. There was a wide variation in the collagen concentrations but the mean value (+/- SEM) for patients with CFA (217 +/- 13 mg/g dry weight) was significantly higher (P less than 0.02) than that of the controls (155 +/- 15 mg/g dry weight). The mean collagen concentration of the autopsy samples (243 +/- 20 mg/g dry weight) was significantly higher (P less than 0.05) than that of the biopsy samples (165 +/- 24 mg/g dry weight). The mean total collagen was markedly raised (P less than 0.001) in right lungs of patients with CFA (32.5 +/- 4.3 g) compared with normal lungs (14.0 +/- 1.1 g). When corrected for the predicted lung volume this difference in total lung collagen remained statistically significant (P less than 0.01, mean for patients 4.7 +/- 0.7 mg/ml, controls 2.3 +/- 0.2 mg/ml). These results demonstrate an increased deposition of lung collagen in this form of pulmonary fibrosis. They also suggest that there is a greater collagen concentration in lungs of patients with later disease, indicating a progressive deposition of collagen during the course of the disease.

Influenza Promotes Collagen Deposition via αvβ6 Integrin-mediated Transforming Growth Factor β Activation

“…Our data suggest that lung collagen can be deposited in the lung of virally infected mice as early as 5 days post-infection. Although we are not proposing that influenza infection causes pulmonary fibrosis, it is evident that key mechanisms involved in the development of fibrosis, including ␣v␤6-mediated TGF␤ activation (4,68), epithelial apoptosis (25), and lung collagen deposition (69), are triggered by influenza infection and may thus promote fibrogenesis in an appropriately susceptible host. In conclusion, the results described herein provide a novel mechanism through which pulmonary infection with influenza virus can result in the activation of TGF␤ via a Smad3-, TLR3-, and ␣v␤6 integrin-dependent pathway.…”

A monoclonal antibody to the carboxyterminal domain of procollagen type I visualizes collagen-synthesizing fibroblasts. Detection of an altered fibroblast phenotype in lungs of patients with pulmonary fibrosis.

“…Moreover, in active pulmonary fibrosis, the number of fibroblasts staining for procollagen and their average intracellular collagen content (and almost certainly their synthetic activity) is increased. Thus, it appears clear from this and related studies that unknown factors in pulmonary fibrosis stimulate both increased numbers offibroblasts and a more active fibroblast synthetic phenotype (1,3,21,22). Lung fibroblasts staining with Anti-pC could contain more procollagen than fibroblasts from quiescent lung simply because procollagen secretion is somehow impeded, as in the case of ascorbate deprivation (23).…”

“…Whereas in many cases the etiology is clear, cases are frequently of unknown cause, thus creating a significant therapeutic dilemma. Although the pathophysiologic mechanisms remain unclear, progressive connective tissue deposition characterizes fibrotic lung disorders (1). Histopathological and clinical findings currently guide therapy (2) but there is a clear need for more objective methods to assess disease activity.…”

“…Determining collagen content oflung biopsies is not a reliable guide to disease activity. In addition to the obvious methodological difficulties, lung collagen may accumulate slowly or explosively, or even exist in excessive quantities as a result of prior disease activity (1,3,4). Furthermore, chemically detectable increases in collagen content may occurr relatively late and thus may not be detectable as a result offocal fibroproliferative reactions.…”

Second harmonic generation microscopy analysis of extracellular matrix changes in human idiopathic pulmonary fibrosis

“…3 Areas of dense collagen accumulation (old scar) are juxtaposed with fibroblastic foci (new scar formation). Collagen I and other minor isoforms (type III, V) are the primary components of the new abnormal matrix, [3][4][5][6] where the balance changes during progression. For example, previous studies have found that collagen III is characteristic of early IPF, whereas collagen I dominates in late-stage disease.…”