Open AccessLocalized expression of tenascin in systemic sclerosis–associated pulmonary fibrosis and its regulation by insulin‐like growth factor binding protein 3
Author(s) -
Brissett Monique,
Veraldi Kristen L.,
Pilewski Joseph M.,
Medsger Thomas A.,
FeghaliBostwick Carol A.
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.30647
Subject(s) - pulmonary fibrosis , fibrosis , tenascin c , growth factor , lung , transforming growth factor , medicine , pathology , respiratory disease , insulin like growth factor binding protein , immunohistochemistry , endocrinology , insulin like growth factor , receptor
Objective To determine the role of insulin‐like growth factor binding protein 3 (IGFBP‐3) in mediating the effects of transforming growth factor β (TGFβ) on tenascin‐C (TN‐C) production and to assess the levels of TN‐C in vivo in patients with systemic sclerosis (SSc)–associated pulmonary fibrosis. Methods Human primary lung fibroblasts were stimulated with TGFβ or IGFBP‐3 in the presence or absence of specific small interfering RNAs and chemical inhibitors of the signaling cascade. TN‐C levels in lung tissue specimens obtained from patients with SSc‐associated pulmonary fibrosis were assessed using immunohistochemical analysis and were compared with the levels in specimens obtained from normal donors. TN‐C levels were quantified in sera from normal donors and patients with SSc with or without pulmonary fibrosis, using an enzyme‐linked immunosorbent assay. Results IGFBP‐3 mediated the induction of TN‐C by TGFβ. Direct induction of TN‐C by IGFBP‐3 occurred in a p38 MAP kinase–dependent manner. TN‐C levels were abundant in lung tissues from patients with SSc and were localized to subepithelial layers of the distal airways. No TN‐C was detectable around the proximal airways. Patients with SSc‐associated pulmonary fibrosis had significantly higher levels of circulating TN‐C compared with SSc patients without pulmonary fibrosis. Longitudinal samples obtained from patients with SSc before and after the onset of pulmonary fibrosis showed increased levels of TN‐C after the onset of pulmonary fibrosis. Conclusion IGFBP‐3, which is overexpressed in fibrotic lungs, induces production of TN‐C by subepithelial fibroblasts. The increased lung tissue levels of TN‐C parallel the levels detected in the sera of SSc patients with pulmonary fibrosis, suggesting that TN‐C may be a useful biomarker for SSc‐related pulmonary fibrosis.