Secretoglobin 3A2 Suppresses Bleomycin-induced Pulmonary Fibrosis by Transforming Growth Factor β Signaling Down-regulation

Abstract

With increasing worldwide rates of morbidity and mortality of pulmonary fibrosis, the development of effective therapeutics for this disease is of great interest. Secretoglobin (SCGB) 3A2, a novel cytokine-like molecule predominantly expressed in pulmonary airways epithelium, exhibits anti-inflammatory and growth factor activities. In the current study SCGB3A2 was found to inhibit TGF␤-induced differentiation of fibroblasts to myofibroblasts, a hallmark of the fibrogenic process, using pulmonary fibroblasts isolated from adult mice. This induction was through increased phosphorylation of STAT1 and expression of SMAD7 and decreased phosphorylation of SMAD2 and SMAD3. To demonstrate the effect of SCGB3A2 on the TGF␤ signaling in vivo, a bleomycin-induced pulmonary fibrosis mouse model was used. Mice were administered bleomycin intratracheally followed by intravenous injection of recombinant SCGB3A2. Histological examination in conjunction with inflammatory cell counts in bronchoalveolar lavage fluids demonstrated that SCGB3A2 suppressed bleomycin-induced pulmonary fibrosis. Microarray analysis was carried out using RNAs from lungs of bleomycin-treated mice with or without SCGB3A2 and normal mice treated with SCGB3A2. The results demonstrated that SCGB3A2 affects TGF␤ signaling and reduces the expression of genes involved in fibrosis. This study suggests the potential utility of SCGB3A2 for targeting TGF␤ signaling in the treatment of pulmonary fibrosis.

ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling

“…Smad2 and Itgb8 message upregulation, as well as decreased scgb3a2 levels, suggests that that TGF-␤ signaling is active in the lung MSC. Secretoglobin3A2 (scgb3a2) inhibits TGF-␤-induced myofibroblast differentiation in part via regulation of SMAD2 (56). SMAD 2 mediates TGF-␤ signaling while integrin subunit beta8 (Itgb8) expression is increased with inflammation and results in TGF-␤ activation (with ␣ v subunit) by fibroblasts (41,61).…”

Secretoglobin Superfamily Protein SCGB3A2 Alleviates House Dust Mite-Induced Allergic Airway Inflammation in Mice

“…SCGB3A2 is predominantly expressed in the epithelial cells of the trachea, bronchus, and bronchiole of lung [4]. SCGB3A2 plays a role in embryonic lung development, and inflammation and fibrosis of lung [5–11]. SCGB3A2 is also suggested as a candidate marker for lung adenocarcinoma [12, 13].…”

Noninvasive Monitoring of Pulmonary Fibrosis by Targeting Matrix Metalloproteinases (MMPs)

“…1B, right). 29, 31 The levels of Mmp2 mRNA increased by 4.25±0.84, 6±1.05, and 9±1.87 folds, respectively on day 7, 14, and 21 days post-BLM administration, as compared with PBS-treated control lungs as determined by qRT-PCR (Fig. 1C).…”

“…Recombinant mouse SCGB3A2 was prepared as previously described. 29 All other solvents and reagents were purchased from Sigma-Aldrich (St. Louis, MO).…”