Bilirubin decreases NOS2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats

Abstract

We investigated a possible beneficial role for bilirubin, one of the products of heme degradation by the cytoprotective enzyme heme oxygenase-1 in counteracting Escherichia coli endotoxin-mediated toxicity. Homozygous jaundice Gunn rats, which display high plasma bilirubin levels due to deficiency of glucuronyl transferase activity, and Sprague-Dawley rats subjected to sustained exogenous bilirubin administration were more resistant to endotoxin (LPS)-induced hypotension and death compared with nonhyperbilirubinemic rats. LPS-stimulated production of nitric oxide (NO) was significantly decreased in hyperbilirubinemic rats compared with normal animals; this effect was associated with reduction of inducible NO synthase (NOS2) expression in renal, myocardial, and aortic tissues. Furthermore, NOS2 protein expression and activity were reduced in murine macrophages stimulated with LPS and preincubated with bilirubin at concentrations similar to that found in the serum of hyperbilirubinemic animals. This effect was secondary to inhibition of NAD(P)H oxidase since 1) inhibition of NAD(P)H oxidase attenuated NOS2 induction by LPS, 2) bilirubin decreased NAD(P)H oxidase activity in vivo and in vitro, and 3) down-regulation of NOS2 by bilirubin was reversed by addition of NAD(P)H. These findings indicate that bilirubin can act as an effective agent to reduce mortality and counteract hypotension elicited by endotoxin through mechanisms involving a decreased NOS2 induction secondary to inhibition of NAD(P)H oxidase.

Phycocyanin and phycocyanobilin fromSpirulina platensisprotect against diabetic nephropathy by inhibiting oxidative stress

“…These data suggested that the effect of phycocyanin may be mediated by that of phycocyanobilin. Although the antioxidant effects of bilirubin are due to its strong radical scavenging activity, several reports have shown that bilirubin directly inhibits NAD(P)H oxidase activity (19,20). Interestingly, we and other investigators have shown that nonphagocytic NAD(P)H oxidases may be the main sources of ROS in the vascular tissues of diabetic animals and patients (11,13,16,18).…”

Potential complementarity of high-flavanol cocoa powder and spirulina for health protection

“…While spirulina -once harvested as a food by the Aztecs, and still used by Africans living near Lake Chad -has been popular as a supplement in "health food" circles for several decades, its true health-protective merit has only recently been discovered: phycocyanobilin (PCB), the chromophore bound to spirulina's chief protein, phycocyanin, can function as a potent inhibitor of NADPH oxidase, the enzyme complex that is the chief source of pathological oxidant stress in a wide range of health disorders. 51,52 In this regard, it appears to mimic the physiological activity of free bilirubin; [53][54][55][56] PCB can be converted within cells to phycocyanorubin, which is nearly identical in structure to bilirubin. 57 Although the clinical utility of ample intakes of spirulina has so far received little research attention, in numerous rodent studies orally administered spirulina or phycocyanin has shown potent anti-inflammatory, cytoprotective, and anti-atherogenic activities; these effects are most likely attributable to down-regulation of NADPH oxidase activity.…”

Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

“…It displays anti-inflammatory activity in animal models of endotoxemia, septicemia and ischemia reperfusion injury (Fondevila et al, 2004;Wang et al, 2004;Keshavan et al, 2005;Lanone et al, 2005;Nakao et al, 2005;Overhaus et al, 2006;Kadl et al, 2007). Some of the proposed mechanisms of bilirubin including its ability to down-regulate expression of adhesion molecules, inhibit infiltration of inflammatory cells and production of nitric oxide (NO), and to reduce production of various inflammatory factors.…”