EXPRESSION OF INSULIN-LIKE-GROWTH-FACTOR BINDING-PROTEINS IN BRONCHOALVEOLAR LAVAGE FLUID OF PATIENTS WITH PULMONARY SARCOIDOSIS

Pulmonary sarcoidosis involves development of parenchymal granulomata that usually resolve spontaneously; however, it remains unclear what p athogenic mechanisms are responsible for the progression to local or d iffuse fibrosis with irreversible lung remodeling that occurs in 20% o f patients. Alveolar macrophages have a pivotal role in sarcoidosis, r eleasing mediators including insulin-like growth factor (IGF)-1, a pot ent profibrogenic molecule. IGF-I bioavailability in the lung is depen dent on at least six high-affinity IGF-binding proteins (IGFBP), which mainly inhibit IGF-1 action. We have investigated their presence in p atients with established stage III sarcoidosis to determine whether IG F-1 and IGFBP contribute to the fibrogenic process in these patients a nd as such contribute to the (clinical) progression of the disease. Th e fibroblast mitogenic potential of bronchoalveolar lavage fluid (BALF ) was more than 3-fold higher (P < 0.005) in sarcoid patients. Sarcoid BALF-induced activity could be inhibited (P < 0.0005) by neutralizing antibodies to IGF-1. We established the IGFBP profile of BALF with We stern ligand analysis and quantified expression of IGFBP-3 by immunobl otting. IGFBP-2 and IGFBP-4 predominate in normal and sarcoid BALF, bu t IGFBP-3 occurs only as a modified, smaller, 29-kD form, expression o f which was raised (P < 0.003) in sarcoid patients. Gene expression of IGF-1 and IGFBP-3 was demonstrated by reverse transcription-polymeras e chain reaction in BAL cells. Thus, local production of pro-fibrogeni c IGF-I may be subject to substantial post-translational regulation by associated IGFBP and IGFBP proteases that may contribute to enhanced fibrogenesis in sarcoidosis patients with evidence of progression or ( development) of fibrosis.