Antifibrotic Role of HGF in Sarcoidosis

Abstract

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.