Chronic Alcohol Ingestion Primes the Lung for Bleomycin-Induced Fibrosis in Mice

Abstract

Background Alcohol abuse increases the risk for acute lung injury (ALI). In both experimental models and in clinical studies, chronic alcohol ingestion causes airway oxidative stress and glutathione depletion and increases the expression of transforming growth factor beta-1 (TGFβ1), a potent inducer of fibrosis, in the lung. Therefore, we hypothesized that alcohol ingestion could promote aberrant fibrosis following experimental ALI and that treatment with the glutathione precursor s-adenosylmethionine (SAMe) could mitigate these effects. Methods Three month old C57BL/6 mice were fed standard chow ± alcohol (20% v/v) in their drinking water for 8 wks and ± SAMe (4% w/v) during the last 4 wks. ALI was induced by intratracheal instillation of bleomycin (2.5 units/kg) and lungs were assessed histologically at 7 and 14 days for fibrosis, and at 14 days for the expression of extracellular matrix proteins and TGFβ1. Results Alcohol ingestion had no apparent effect on lung inflammation at 7 days, but at 14 days after bleomycin treatment it increased lung tissue collagen deposition, hydroxyproline content, and the release of activated TGFβ1 into the airway. In contrast, SAMe supplementation completely mitigated alcohol-induced priming of these aberrant fibrotic changes through decreased TGFβ1 expression in the lung. In parallel, SAMe decreased alcohol-induced TGFβ1 and Smad3 mRNA expressions by lung fibroblasts in vitro. Conclusion These new experimental findings demonstrate that chronic alcohol ingestion renders the experimental mouse lung susceptible to fibrosis following bleomycin-induced ALI, and that these effects are likely driven by alcohol-mediated oxidative stress and its induction and activation of TGFβ1.

Reactive oxygen species and fibrosis: further evidence of a significant liaison

“…In addition, the response to high-fat diets or chronic alcohol abuse appears to involve the suppression of NRF2. Indeed, the onset of bleomycin-induced lung fibrosis in mice has been found to be primed by chronic alcohol abuse; the priming effect is considered to be the result of the reduced expression of the NRF2-dependent genes for GST theta 2 and the catalytic subunit of glutamate-cysteine ligase and of the increased expression of TGF-β1 (Sueblinvong et al 2014a). The increased TGF-β1 expression upon alcohol ingestion in this model has subsequently been shown to be the dominant modulator, since the blocking of the TGF-β1 signal attenuates the alcohol-induced suppression of NRF2 (Sueblinvong et al 2014b).…”

Chronic Alcohol Ingestion and Predisposition to Lung “Cirrhosis”

“…In this issue of the Journal, Sueblinvong and colleagues extend knowledge in this area by studying the effects of chronic alcohol ingestion (20% alcohol in drinking water for 8 weeks) on the development of lung fibrosis in C57BL/6 mice induced by administration of bleomycin; an agent known to induce lung fibrosis in both humans and rodents (Sueblinvong et al, 2013). Administration of bleomycin directly via tracheal instillation or systemic delivery triggers a massive inflammatory response associated with oxidant stress and edema that is most evident a week after the insult (Mouratis and Aidinis, 2011).…”

Protective influence of hyaluronic acid on focal adhesion kinase activity in human skin fibroblasts exposed to ethanol

“…Medicines that contain this substance are commonly used in treating illnesses accompanied by disorders in the metabolism of ECM components, eg, collagen. Presumably, because of its physical properties, HA binds and inactivates many water-soluble substances, including pro-inflammatory cytokines 4,13. Half of the HA in the human body is located in the epidermis and dermis, where it is synthesized by keratinocytes and fibroblasts.…”