Fig. 3

Possible mechanism through which CS together with hypoxic conditions may act as a potent environmental risk factor for inflammatory and autoimmune diseases. CSCs including heavy metals & various immune-modulators and CS-induced oxidative stress enhance the generation of auto-reactive pro-inflammatory T cells, production of autoantibody (e.g. anti-elastin Abs, anti-dsDNA Abs). Oxidative stress induced by CS also causes various genetic and epigenetic changes (increasing the rate of histone acetylation, demethylation and phosphorylation process at the same time decreasing the deacetylation and methylation process rate) which results in increased and sustained expression of pro-inflammatory genes. Similarly, Hypoxia (hypobaric hypoxia and/or cellular hypoxia) by various mechanisms primarily via increasing the HIF expression, oxidative stress and glycolysis rate (Warberg’s effect) also alters the immunological balance (increasing the expression of pro-inflammatory immune-modulators, B and T cell activity and proliferation while decreasing regulates the Treg cell activity and proliferation). Hence, CS in combination with hypoxia acts as a potent environmental risk factor for inflammatory and autoimmune diseases. Abs. Antibodies; AP-1, Activator protein-1; Cd, Cadmium; CS, Cigarette smoke; CSC, Cigarette smoke constituent; DNMT, DNA methyl transferase; HAT, Histone acetylase; HDAC, Histone deacetylase; HIF, Hypoxia-inducible factor; IL, Interleukin; INF, Interferon; NF-κB, Nuclear factor-kappa B; Ni, Nickel; NK, Natural killer cell; Pb, Lead; RNS, Reactive nitrogen species; ROS, Reactive oxygen species; RBC. Red blood cell; TNF, Tumor necrosis factor