Sunitinib displays pulmonary fibrosis in experimental rats: Role of IL-17A dependent pathway

Abstract

Sunitinib (SUN) is an FDA approved first line drug for management of metastatic renal cancers and advanced cancerous states of gastrointestinal tract, however, side effects including fibrosis has been reported. Secukinumab (Secu) is an immunoglobulin G1 monoclonal antibody that exhibits anti-inflammatory activity by inhibiting several cellular signaling molecules. This study aimed to examine pulmonary protective potential of Secu in SUN-induced pulmonary fibrosis mediated through inhibition of inflammation via targeting IL-17A associated signaling pathway and using pirfenidone (PFD), an antifibrotic drug approved in 2014 for treatment of pulmonary fibrosis with IL-17A as one of its targets, as a reference drug. Wistar rats (160-200g) were divided randomly into 4 groups (n=6); Group 1 served as normal control; Group 2 served as disease control where it was exposed to SUN (25mg/kg; 3 times weekly orally for 28days); Group 3 was administered SUN and Secu (3mg/kg subcutaneous at 0,14 and 28days) and Group 4 was administered SUN and PFD (100mg/kg/day orally for 28days). Pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were measured in addition to components of IL-17A signaling pathway (TGF-β, collagen, hydroxyproline). Results revealed that IL-17A-associated signaling pathway was activated in fibrotic lung tissue induced by SUN. Relative to normal control, SUN administration significantly elevated lung organ coefficient, IL-1β, IL-6, TNF-α, IL-17A, TGF-β, hydroxyproline and collagen expression. Secu or PFD treatment restored the altered levels to nearly normal values. Our study indicates that IL-17A participates in the development and progression of pulmonary fibrosis in a TGF-β dependent manner. Hence, components of IL-17A signaling pathway represent potential therapeutic targets for protection and treatment of fibro-proliferative lung disease.