Vitamin C protect against nicotine induced lung ailment - PROJECT SUMMARY Smoking has been demonstrated to induce oxidative stress, which is compounded with significantly reduced antioxidant availability, increased production of inflammatory cytokines as well as neutrophilic infiltration that are implicated in pathogenic processes in the lungs. Additionally, studies involving mice exposed to cigarette smoke reveal impaired pulmonary anti-bacterial and anti-viral defenses in response to infections. Other research has found that smokers also exhibit increased susceptibility to infections including influenza and SARS-CoV2. Investigations concerning the harmful effects that tobacco use exerts to lower bodily defenses are undeniably urgent, particularly those that address strategies for amelioration of smoking-induced health risks. Nicotine is the main component among the thousands of chemicals in all tobacco products including e-cigarettes. Nicotine binds to a family of nicotinic acetylcholine receptors (nAChRs) like acetylcholine (ACh). nAChRs are highly expressed in the lung fibroblasts and epithelial cells. Nicotine functions as an immunomodulator and has been reported to impair the immune response of smokers to infections. Vitamin C (vitC; ascorbic acid: AA) is an essential water- soluble vitamin with known respiratory health enhancing properties. Humans cannot synthesize vitC endogenously and thus obtain it from dietary sources via intestinal absorption. Dietary vitC is absorbed from the intestine via carrier-mediated sodium-dependent vitC transporters (SVCT1 and SVCT2, the products of the SLC23A1 and SLC23A2 genes, respectively). Low plasma levels of vitC have been found in patients with viral infections and other critical illnesses. Many previous studies have highlighted the role of vitC in protection against lung infections. Administration of vitC to patients with pneumonia, for example, can reduce the severity and duration of the disease. Pneumonia and influenza infections and related pathologies are also more severe in Gulo KO mice (a mouse model that cannot synthesize vitC endogenously, similar to humans). Both smokers and passive smokers have lower plasma and leukocyte vitC levels than non-smokers. Mean serum concentrations of vitC in adults who smoke have been found to be one-third lower than those of non-smokers. Our preliminary studies showed that nicotine reduces the functional expression of vitC transporters in the intestine and lung epithelial cells. We therefore hypothesize that nicotine induced vitC deficiency/insufficiency is a major factor in increasing the risk of respiratory viral infections in smokers. To test this hypothesis we propose two specific aims: Aim 1: To determine the mechanisms underlying nicotine-mediated impaired uptake of vitC by intestinal and lung epithelial cells using in vitro and in vivo models. Aim 2: To determine whether vitC supplementation is able to overcome the increased susceptibility to viral infections induced by nicotine. The expected outcomes of this project will advance our knowledge regarding the changes in uptake of vitC in the intestine and in the lungs, which is essential to develop novel therapeutics to improve vitC deficiency and insufficiency while also addressing ensuing lung viral infections and injury found in smoking population.
