Role of NO in enhancing the expression of HO-1 in LPS-stimulated macrophages

Macrophages serve as the first-line defense against invading pathogens by (a) overproducing O₂ ^- via activation of NADPH-oxidase localized in its plasma membrane, (b) inducing the expression of inducible nitric oxide synthase (iNOS) and overproducing NO, and (c) generating highly toxic peroxynitrite (ONOO^-) to kill the invading pathogens without killing the macrophages themselves. Results show that this was due at least in part to the NO-derived induction of heme oxygenase-1 (HO-1) expression. The NO-derived induction of HO-1 caused (a) rapid elimination of toxic heme to inhibit lipid peroxidation and to prevent further induction of iNOS, (b) rapid production of bile pigment antioxidants to scavenge reactive oxygen (O ₂ ^-) and nitrogen (NO) metabolites, and (c) rapid production of carbon monoxide (CO) to inhibit further production of O ₂ ^- and NO by blocking the activities of NADPH-oxidase and iNOS, respectively. Thus, the NO overproduced by the O₂ ^- dependent induction of iNOS expression can scavenge O₂ ^- to produce ONOO^-, first to kill the invading pathogens and second to enhance the HO-1 expression in macrophages. This allows the survival of host tissues from the injuries caused by inflammatory oxidative stress.