1. Academic Validation
  2. The Integrin Inhibitor Cilengitide and Bleomycin-Induced Pulmonary Fibrosis : Cilengitide and Bleomycin-Induced Pulmonary Fibrosis

The Integrin Inhibitor Cilengitide and Bleomycin-Induced Pulmonary Fibrosis : Cilengitide and Bleomycin-Induced Pulmonary Fibrosis

  • Lung. 2020 Dec;198(6):947-955. doi: 10.1007/s00408-020-00400-y.
Jeffrey D Ritzenthaler 1 Michael Zhang 2 3 Edilson Torres-Gonzalez 4 Jesse Roman 2 5 4 6
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Pulmonary, Allergy and Critical Medicine, Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, 381, Philadelphia, PA, 19107, USA. jeffrey.ritzenthaler@jefferson.edu.
  • 2 Department of Pharmacology & Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA.
  • 3 University of Minnesota Medical School, Minneapolis, MN, USA.
  • 4 Department of Medicine, Division of Pulmonary, Allergy and Critical Medicine, Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Jefferson Alumni Hall, 381, Philadelphia, PA, 19107, USA.
  • 5 Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville Health Sciences Center, Louisville, KY, USA.
  • 6 Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
Abstract

Purpose: Fibroproliferation and excess deposition of extracellular matrix (ECM) are the pathologic hallmarks of idiopathic pulmonary fibrosis (IPF), a chronic progressive disorder with high mortality and suboptimal treatment options. Although the etiologic mechanisms responsible for the development and progression of IPF remain unclear, cell-ECM interactions and growth factors are considered important. Cilengitide is a cyclic RGD pentapeptide with anti-angiogenic activity that targets αvβ3, αvβ5 and α5β1, integrins known to mediate cell-ECM interactions and activate the pro-fibrotic growth factor Transforming Growth Factor beta (TGF-β).

Methods: Cilengitide was studied in vitro with the use of NIH/3T3 cells and primary lung fibroblasts, and in vivo in the well-characterized bleomycin-induced lung injury model. The extent of ECM deposition was determined by RT-PCR, Western blot, histologic analysis and hydroxyproline assay of lung tissue. Bronchoalveolar lavage analysis was used to determine cell counts.

Results: Cilengitide treatment of cultured fibroblasts showed decreased adhesion to vitronectin and fibronectin, both integrin-dependent events. Cilengitide also inhibited TGF-β-induced fibronectin gene expression and reduced the accumulation of mRNAs and protein for fibronectin and collagen type I. Both preventive and treatment effects of daily injections of cilengitide (20 mg/kg) failed to inhibit the development of pulmonary fibrosis as determined by histological analysis (Ashcroft scoring), bronchoalveolar lavage (BAL) fluid cell counts, and hydroxyproline content.

Conclusions: Overall, our data suggest that, despite its in vitro activity in fibroblasts, daily injections of cilengitide (20 mg/kg) did not inhibit the development of or ameliorate bleomycin-induced pulmonary fibrosis in mice.

Keywords

Bleomycin; Cilengitide; Fibrosis; Integrins; Lung injury.

Figures
Products