Scholarlink

Background <p>Injury-repair responses typically induce tissue or organ scarring. Generally, cAMP-mobilizing agents inhibit the activation of fibroblasts and deposition of extracellular matrix. Some but not all cAMP-mobilizing agents inhibit fibrosis. Evidence suggests that inhaled treprostinil, a prostacyclin (IP) analog, increases intracellular cAMP levels [cAMP]<sub>I</sub>, and slows the decline in pulmonary function in patients with idiopathic pulmonary fibrosis (IPF). However, the molecular mechanisms by which cAMP-mobilizing agents, including treprostinil, alter the expression of matrix proteins in human lung fibroblasts (HLF) remain unclear. Unlike other G<sub>αs</sub> -coupled receptors, we posit that the antifibrotic properties of treprostinil are driven by cAMP-mobilizing-dependent and -independent responses mediated by the IP receptor activation.</p> Methods <p>As a model of lung fibrosis, primary&#xa0;HLF derived from non-IPF and IPF donors were stimulated with TGF-β; collagen 1A1 and plasminogen activator inhibitor-1 (PAI) expression were then measured in the presence and absence of cAMP mobilizing agents. The necessity of receptor activation for inhibiting TGF-β-induced markers of fibrosis was determined by using soluble receptor inhibitors and decreasing receptor expression with siRNA.</p> Results <p>Treprostinil decreased TGF-β-induced extracellular matrix production by HLF, and the magnitude of the inhibition was greater than that of other cAMP-mobilizing GPCR agonists despite these agents comparably increasing cAMP levels. There was no difference in the sensitivity and magnitude of the treprostinil inhibition in HLF derived from non-fibrosis and lung fibrosis donors. Treprostinil inhibition of TGF-β-induced collagen 1A1and PAI-1 was mediated through the activation of the IP receptor. The activation of the EP2 receptor, in part, inhibited TGF-β-induced collagen 1A1 expression by treprostinil or prostaglandin E2. β2 agonists had little effect on TGF-β-induced expression of collagen 1A1 and PAI-1. The inhibitory effects of treprostinil on TGF-β-induced collagen 1A1 expression required G<sub>αs</sub> activation, while G<sub>αs</sub> only partially mediated treprostinil inhibition of PAI-1.</p> Conclusion <p>The anti-fibrotic properties of treprostinil are primarily mediated by the IP receptor, acting through both G<sub>αs</sub>-dependent and -independent pathways. Understanding the differential effects of cAMP-mobilizing pathways on HLF fibrotic signatures can provide insight into developing novel targets to manage IPF.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The differential effects of cAMP mobilizing agents on TGF-β-induced extracellular matrix in human lung-derived fibroblasts: insights into therapeutic targets for lung fibrosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月22日

查看全文
  • Sarah Orfanos,
  • Brian T. Deeney,
  • Gaoyuan Cao,
  • Nikhil Karmacharya,
  • Anjani Ravi,
  • Cynthia J. Koziol-White,
  • Qi Yang,
  • Rennolds S. Ostrom,
  • Reynold A. Panettieri Jr.

摘要

Background

Injury-repair responses typically induce tissue or organ scarring. Generally, cAMP-mobilizing agents inhibit the activation of fibroblasts and deposition of extracellular matrix. Some but not all cAMP-mobilizing agents inhibit fibrosis. Evidence suggests that inhaled treprostinil, a prostacyclin (IP) analog, increases intracellular cAMP levels [cAMP]I, and slows the decline in pulmonary function in patients with idiopathic pulmonary fibrosis (IPF). However, the molecular mechanisms by which cAMP-mobilizing agents, including treprostinil, alter the expression of matrix proteins in human lung fibroblasts (HLF) remain unclear. Unlike other Gαs -coupled receptors, we posit that the antifibrotic properties of treprostinil are driven by cAMP-mobilizing-dependent and -independent responses mediated by the IP receptor activation.

Methods

As a model of lung fibrosis, primary HLF derived from non-IPF and IPF donors were stimulated with TGF-β; collagen 1A1 and plasminogen activator inhibitor-1 (PAI) expression were then measured in the presence and absence of cAMP mobilizing agents. The necessity of receptor activation for inhibiting TGF-β-induced markers of fibrosis was determined by using soluble receptor inhibitors and decreasing receptor expression with siRNA.

Results

Treprostinil decreased TGF-β-induced extracellular matrix production by HLF, and the magnitude of the inhibition was greater than that of other cAMP-mobilizing GPCR agonists despite these agents comparably increasing cAMP levels. There was no difference in the sensitivity and magnitude of the treprostinil inhibition in HLF derived from non-fibrosis and lung fibrosis donors. Treprostinil inhibition of TGF-β-induced collagen 1A1and PAI-1 was mediated through the activation of the IP receptor. The activation of the EP2 receptor, in part, inhibited TGF-β-induced collagen 1A1 expression by treprostinil or prostaglandin E2. β2 agonists had little effect on TGF-β-induced expression of collagen 1A1 and PAI-1. The inhibitory effects of treprostinil on TGF-β-induced collagen 1A1 expression required Gαs activation, while Gαs only partially mediated treprostinil inhibition of PAI-1.

Conclusion

The anti-fibrotic properties of treprostinil are primarily mediated by the IP receptor, acting through both Gαs-dependent and -independent pathways. Understanding the differential effects of cAMP-mobilizing pathways on HLF fibrotic signatures can provide insight into developing novel targets to manage IPF.