Increased Procollagen III Aminoterminal Peptide-related Antigens and Fibroblast Growth Signals in the Lungs of Patients with Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by an increased density of inflammatory cells, fibroblasts, and collagen within the lung parenchyma. To gain insights into the mechanisms leading to the increased density of fibroblasts and altered collagen metabolism in the IPF lung, bronchoalveolar lavage fluid from normal subjects and patients with IPF or sarcoidosis was analyzed for (1) the presence of antigenic material related to the aminoterminal propeptide domain of type III procollagen, and (2) fibroblast growth-promoting activity in the extracellular milieu of the lower respiratory tract. Whereas bronchoalveolar lavage fluid (BALF) type III procollagen aminoterminal peptide-related antigen levels in 59 patients with sarcoidosis were similar to the levels of control subjects (p > 0.10), 31 patients with IPF had markedly increased levels (12-fold over controls; p < 0.025, IPF versus controls; p < 0.01, IPF versus sarcoidosis). Type III procollagen aminoterminal peptide-related antigen levels correlated with an increase in the ability of BALF to stimulate fibroblast proliferation (p < 0.05). Furthermore, BALF from patients with IPF markedly stimulated human lung fibroblast proliferation in vitro (199% increase, p < 0.01), whereas lavage fluid from patients with sarcoidosis and from control subjects did not. The enhanced fibroblast proliferation induced by IPF BALF occurred in the absence of serum and exogenous growth factors, suggesting that both competence- and progression-type growth factors were present in the lavage fluid. We conclude that the extracellular milieu of the lower respiratory tract in IPF contains increased levels of type III procollagen peptide-related antigens and sufficient growth-promoting signals to stimulate fibroblast proliferation in the absence of exogenous growth factors. Whether the increased growth-promoting activity in the extracellular milieu contributes to the abnormal type III procollagen metabolism in IPF is unknown.