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  • br Results br Discussion Control of chronic inflammation is

    2024-06-08


    Results
    Discussion Control of chronic inflammation is important in several inflammatory conditions like asthma, rheumatoid arthritis and fibrosis in lung diseases. The regulatory pathways that control chronic inflammation are complex and multi-factorial. Over expression of inflammatory mediators such as inflammatory cytokines, matrix metalloproteinase's (MMPs) and cyclo‑oxygenase (COX-2) reflects chronic inflammation pathology. Therefore these inflammatory mediators are important potential targets for therapeutic intervention (Sakane et al., 1997). Dexamethasone (DEX) is a potent long-lasting synthetic glucocorticoid known to inhibit the inflammatory cascade. Because of its potent anti-inflammatory effects, it is widely used to treat a variety of acute and chronic inflammatory diseases including acute lung inflammation, asthma, and rheumatoid arthritis (Kumar et al., 2003, Goulding, 2004). Glucocorticoids regulate many biological processes through their intracellular glucocorticoid receptors. Following glucocorticoid diffusion through the cell membrane bind to its receptors and the activated hormone and glucocorticoid receptor complex translocated into the nucleus and repress transcription factors responsible for the expression of inflammatory mediators (Stahn et al., 2007). Hence understanding the mode of action of glucocorticoids plays a central role in the treatment and development of drugs. Dexamethasone a potent anti-inflammatory and immunosuppressive glucocorticoid is widely used in the treatment of chronic inflammatory diseases (Barnes, 2006, Hillier, 2007). Studies have shown that dexamethasone inhibits the expression of inflammatory mediators in animal models of acute neural injury indicates the action on central nervous system (CNS) efficacy (Kurkowska-Jastrzebska et al., 2004, Zhang et al., 2007). Several in vitro studies show that the cytokine induced expression of eotaxin, IL-6, IL-8, GM-CSF, and RANTES were decreased by glucocorticoids (Levine et al., 1993, Kwon et al., 1995, Stellato et al., 1995). Hence in the present study, we analyzed the effect of dexamethasone on inflammatory mediators and AP-1 factors in PMA or LPS stimulated lung epithelial cells. It is a well-known fact; during bacterial infection the epithelial homoharringtonine present at the mucosal surface are capable of secreting chemo attractants and pro-inflammatory cytokines, the important mediators in lung inflammation. Hence the lung epithelial cells acts as an important site for glucocorticoid action in asthma and other lung inflammatory diseases (Devalia and Davies, 1993). In our study dexamethasone up to 1μM concentration show no effect on the cell viability, suggested homoharringtonine that the steroids at low concentrations does not exhibit cytotoxic effect in lung cells. Nitric oxide (NO) is a short-lived, readily diffusible molecule of great biological importance. It plays a key role in signal transduction, neurotransmission, and host-defense mechanism. NO is produced by nitric-oxide synthases (Alderton et al., 2001, Bermudez et al., 2002) and is highly reactive gaseous mediator involved in many physiologic processes its extensive production lead to various inflammatory diseases (Bogdan, 2001). Hence, the decreased production of nitric oxide is regarded as a therapeutic target for inflammation. In our study A549 cells treated with PMA has no effect on NO production, while LPS induced the NO production. However the treatment of cells with dexamethasone significantly decreased the LPS induced NO production in a dose dependent manner suggesting the anti-inflammatory activity of dexamethasone. Our results are in good agreement with earlier studies reported by Takashi Ozaki et al. who reported that dexamethasone inhibits the NO production in pro-inflammatory cytokine-stimulated hepatocytes (Ozaki et al., 2010). Inducible nitric oxide synthase (iNOS) is elevated in many inflammatory diseases of the respiratory tract. One of the potential mechanisms by which dexamethasone pretreatment inhibited LPS induced lung inflammation may be a decrease in iNOS expression, suggesting that inducible isoform of NOS is responsible for the excess production of NO in LPS induced sepsis in animals (Trifilieff et al., 2000). Studies are reported that in both animal models and humans that LPS stimulates iNOS expression and NO over-production, which damages lung tissue through peroxynitrite formation (Razavi et al., 2002). In our present study, the elevated iNOS expressions were detected in the cells treated with LPS alone whereas the pretreatment of cells with dexamethasone significantly inhibited the LPS induced mRNA level of iNOS suggesting the inhibitory activity of dexamethasone on LPS-induced NO production was also reflected with the suppression of iNOS mRNA expression level as shown by semi-quantitative RT-PCR. Similar studies were reported in endotoxin-induced acute lung injury where dexamethasone shows protective effect through inhibiting expression of iNOS (Yu et al., 2009).