s-allylcysteine and Pulmonary-Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by inflammation, multifocal fibrotic lesions and excessive collagen deposition with limited therapies. As a major bioactive compound in garlic, S-allyl-l-cysteine (SAC) is a neuroprotective drug candidate to prevent cognitive decline, however, its anti-pulmonary fibrotic activity remains unknown. Here, we investigated whether SAC could attenuate bleomycin (BLM)-induced pulmonary fibrosis and inflammation in mice. Our results showed that SAC dose-dependently reduced the infiltration of inflammatory cells, pulmonary lesions and collagen deposition in BLM treated mice with downregulated mRNA expression levels of fibrotic genes including alpha smooth muscle actin (α-SMA), fibronectin, collagen I and collagen III as well as the protein level of α-SMA. In addition, SAC could also reduce the mRNA expression of inflammatory mediators such as TNF-α and iNOS. Furthermore, higher phosphorylation of AKT and NF-κB p65 in IPF patient samples and murine samples was verified by immunohistochemistry while SAC could decrease the phosphorylation level of AKT and NF-κB p65 in mice stimulated with BLM. These findings, for the first time, indicate that SAC might mediate AKT/NF-κB signaling pathway to inhibit BLM-induced pulmonary fibrosis and support the potential role of SAC as an anti-pulmonary fibrosis agent.

Topics: Actins; Animals; Bleomycin; Collagen; Cysteine; Dose-Response Relationship, Drug; Fibronectins; Gene Expression; Inflammation; Inflammation Mediators; Mice; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; RNA, Messenger; Signal Transduction

Topics: Animals; Bleomycin; Cell Differentiation; Collagen; Cysteine; Disease Models, Animal; Gene Expression Regulation; Instillation, Drug; Male; Myofibroblasts; Pulmonary Fibrosis; Rats; Transforming Growth Factor beta1

This study examined effects of S-allyl cysteine (SAC) on carbon tetrachloride (CCl4)-induced interstitial pulmonary fibrosis in Wistar rats. CCl4 (0.5 ml/kg) was intraperitoneally injected into rats twice a week for 8 weeks, and SAC (50, 100, or 200 mg/kg), N-acetyl cysteine (NAC, 200 or 600 mg/kg), or L-cysteine (CYS, 600 mg/kg) were orally administrated to rats everyday for 8 weeks. SAC significantly reduced the increases of transforming growth factor beta, lipid peroxides, AST, and ALT in plasma, induced by CCl4. Although CCl4 is mainly metabolized by hepatic cytochrome P450, CCl4 induced systemic inflammation and some organ fibrosis. SAC dose-dependently and significantly attenuated CCl4-induced systemic inflammation and fibrosis of lung. SAC also inhibited the decrease of thiol levels, the increase of inducible nitric oxide synthase expression, the infiltration of leukocytes, and the generation of reactive oxygen species in lungs. Although NAC and CYS attenuated CCl4-induced pulmonary inflammation and fibrosis, the order of preventive potency was SAC > NAC > CYS according to their applied doses. These results indicate that SAC is more effective than other cysteine compounds in reducing CCl4-induced lung injury, and might be useful in prevention of interstitial pulmonary fibrosis.

Topics: Animals; Bronchoalveolar Lavage Fluid; Carbon Tetrachloride; Cysteine; Enzyme Precursors; Glutathione; Hydroxyproline; Liver; Lung; Male; Matrix Metalloproteinase 9; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Pulmonary Fibrosis; Rats; Rats, Wistar; Reactive Oxygen Species; Sulfhydryl Compounds; Transforming Growth Factor beta; Transforming Growth Factor beta1