Expression of Insulin-like Growth Factor Binding Proteins in Bronchoalveolar Lavage Fluid of Patients with Pulmonary Sarcoidosis

Abstract

Pulmonary sarcoidosis involves development of parenchymal granulomata that usually resolve spontaneously; however, it remains unclear what pathogenic mechanisms are responsible for the progression to local or diffuse fibrosis with irreversible lung remodeling that occurs in 20% of patients. Alveolar macrophages have a pivotal role in sarcoidosis, releasing mediators including insulin-like growth factor (IGF)-1, a potent profibrogenic molecule. IGF-1 bioavailability in the lung is dependent on at least six high-affinity IGF-binding proteins (IGFBP), which mainly inhibit IGF-1 action. We have investigated their presence in patients with established stage III sarcoidosis to determine whether IGF-1 and IGFBP contribute to the fibrogenic process in these patients and as such contribute to the (clinical) progression of the disease. The 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 Western ligand analysis and quantified expression of IGFBP-3 by immunoblotting. IGFBP-2 and IGFBP-4 predominate in normal and sarcoid BALF, but IGFBP-3 occurs only as a modified, smaller, 29-kD form, expression of which was raised (P < 0.003) in sarcoid patients. Gene expression of IGF-1 and IGFBP-3 was demonstrated by reverse transcription-polymerase chain reaction in BAL cells. Thus, local production of pro-fibrogenic IGF-1 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.

Insulin-like Growth Factor-I Receptor Blockade Improves Outcome in Mouse Model of Lung Injury

“…In our experiments, IGF-I stimulation selectively activated IRS-2 and the PI3 kinase pathway, and not IRS-1 and the MAPK pathway. Although IGF-I increases proliferation in many cell types (4,18,19,26,27, 31), we did not see any effect of IGF-I on lung fibroblast proliferation. Our results, however, are consistent with the selective activation of IRS-1 and IRS-2 leading to proliferation and migration, respectively, in pleural mesothelioma cells (18) and MCF cells (33).…”

“…In contrast, we used early-passage primary adult lung fibroblasts, which may account for the differences in results. In addition, the mitogenic response to IGF in the earlier studies was determined by immunodepletion of IGF from BALF (26,27). We speculate that activation of fibroblasts by other growth factors or cytokines such as transforming growth factor-b 1 in BALF is necessary for the proproliferative effect of IGF (22,29).…”

“…In our experiments, IGF-I mediated cell survival and migration, but not proliferation, of normal lung fibroblasts through IGF-IR. The prior studies used either the fetal fibroblast cell line IMR-90 or human fetal embryonic fibroblasts (HFL-1) to examine the proliferative response (26,27). In contrast, we used early-passage primary adult lung fibroblasts, which may account for the differences in results.…”

Insulin-Like Growth Factor Binding Proteins 3 and 5 Are Overexpressed in Idiopathic Pulmonary Fibrosis and Contribute to Extracellular Matrix Deposition

“…Spontaneous release of IGFBP-3 in bronchoalveolar lavage cells from patients with IPF was reported, 8 and IGFBP-3 levels are also elevated in the bronchoalveolar lavage fluid and cells of patients with stage III sarcoidosis where it is believed to contribute to fibrogenesis. 16 We have described a 20-fold increase in IGFBP-5 expression and an increase in IGFBP-3 levels in fibroblasts from the fibrotic skin of patients with SSc. 17,18 To address the hypothesis that IGFBPs contribute to the development and/or perpetuation of ECM production and fibrosis in IPF, we determined whether aberrant expression of IGFBP-3 and -5 occurs in IPF lung tissue and in fibroblasts cultured from the lungs of patients with IPF, and whether IGFBP-5 alters matrix production by normal lung fibroblasts.…”

Role of Insulin-like Growth Factor Binding Protein-3 in Allergic Airway Remodeling

“…IGF-I is a potent mitogen and stimulant of collagen secretion in fibroblasts (2), and has been implicated in the pathogenesis of fibrosis in a number of lung disorders (3)(4)(5). IGF-I is up-regulated in the airways of mice after allergen challenge (6), and IGF-I levels in biopsies of patients with asthma correlate with subepithelial fibrosis (7).…”