Protein kinase C θ deletion ameliorates bleomycin-induced pulmonary fibrosis via the improvement of SIRT۱/AMPK signaling on autophagy and senescence

Objective(s): Protein kinase C theta (PKC θ) is involved in the regulation of various inflammatory diseases, such as allergic asthma and ConA-induced hepatitis. However, its role in pulmonary fibrosis has not been reported. This study aimed to explore the role of PKC θ in bleomycin-induced pulmonary fibrosis and the potential mechanisms involved.Materials and Methods: WT C۵۷BL/۶ and PKC-θ deletion mice were administered a single intratracheal injection of bleomycin at a dosage of ۳ mg/kg to prepare an animal model of pulmonary fibrosis. Histopathological changes of lung fibrosis were observed. Blood samples and BALF were collected for biochemical analysis. Protein expression in lung tissues was assessed to investigate a potential mechanism of PKC θ in pulmonary fibrosis.Results: The results suggested that PKC θ knockout improved pulmonary structure and fibrosis through down-regulating the expression of collagen I and fibronectin, and the TGF-β۱ pathway. PKC θ knockout significantly reduced the levels of the inflammatory factors TNF-α, IL-۶, and TGF-β in BALF and lung tissues and the NF-κB/IκB-α pathway in the lung. PKC θ knockout also elevated the activities of antioxidant enzymes SOD and CAT, and improved the SIRT۱/AMPK-HO-۱/Nrf۲ pathway. Further, PKC θ knockout ameliorated the expression of the autophagy-related proteins Beclin ۱ and p۶۲, and the senescence markers p۵۳ and p۲۱.Conclusion: These data showed that the improvement in PKC θ knockout in pulmonary fibrosis was associated with enhanced anti-inflammatory and antioxidant effects, activation of autophagy, and reduced senescence effects.

کلیدواژه ها:

Autophagy ، Protein kinase C &theta ، Pulmonary Fibrosis ، Senescence ، SIRT۱/AMPK signaling- pathway