The reciprocal relationship between heme oxygenase and nitric oxide synthase in the organs of lipopolysaccharide-treated rodents

Abstract

The production of nitric oxide (NO) by inducible NO synthase (NOS) and carbon monoxide (CO) by inducible heme oxygenase (HO) contributes greatly to endotoxemia. Reciprocal relationships have been proposed between the NO/NOS and CO/HO systems. However, the interaction between these systems during endotoxemia is unclear, and it is unknown whether the interactive behavior differs among organs. Using endotoxic rats, we studied the effects of the inducible NOS (iNOS) inhibitor L-canavanine (CAN), and the HO inhibitor zinc protoporphyrin (ZPP) on gene expression and protein levels of iNOS, endothelial NOS (eNOS), inducible HO (HO-1), and constitutive HO (HO-2) in the brain, lung, heart, liver and kidney tissue. Intravenous injection of LPS significantly increased iNOS and HO-1 gene expression in all organs. The effects of LPS on eNOS gene expression differed among organs, with increased expression in the liver and kidney, and no change in the lung, brain and heart. ZPP administration down-regulated the LPS-induced increase in HO-1 expression and produced a further increase in iNOS expression in all organs. These data suggest that the CO/HO system modifies the NO/NOS system in endotoxic organs, and that there were only minor organ-specific behaviors in terms of the relationship between these systems in the organs examined.Endotoxemia, which can lead to shock, is a detrimental consequence of severe Gram-negative bacterial infection. Endotoxic shock is initiated by the release of bacterial cell wall-derived lipopolysaccharide (LPS) and the subsequent production of cytokines and vasoactive mediators (13). Gaseous mediators, namely nitric oxide (NO) and carbon monoxide (CO), and the major endogenous sources of these mediators, nitric oxide synthase (NOS) and heme oxygenase (HO), serve a pivotal role in endotoxemia. NO is an extensively studied molecule, and is known for its vasorelaxation and oxidative stressor properties during endotoxemia and septic shock. NO is produced by three distinct NOS enzymes. Two of these NOS isozymes are predominantly constitutively expressed in endothelial cells (eNOS) and in neuronal cells (nNOS), whereas the expression of the third isozyme (iNOS) is inducible in a variety of cells (e.g., macrophages, hepatocytes, vascular smooth muscle cells and cardiac myocytes) by numerous stimuli, including LPS (5, 13). iNOS is responsible for producing most of the NO that causes hypotension and oxidative stress during endotoxic shock, while eNOS is reported to have only a minor role in the pathophysiology of endotoxemia (9, 18). CO has been perceived for many years to be a life-threatening gas; recently, however, CO has become recognized to have anti-inflammatory and vasorelaxative properties and is essential for life. HO is the rate-limiting enzyme in the catabolism of heme, a process that promotes the formation of equimolar amounts of the bile pigment biliverdin, free iron, and CO (1). Together with the anti-inflam-

Inhibition of lipopolysaccharide-induced liver injury in rats treated with a hepatic drug-metabolizing enzyme inducer p,p′-DDT

“…This is supported by the fact that the decreases in NO levels were suggested to protect against LPS-induced endotoxaemia in rats (Crespo et al, 1999). Interestingly, even though a combined effect of p,p -DDT and LPS treatment on HO-1 expression was not supported by our findings, there is crosstalk between HO-1 and NOS2 induction, demonstrated by the fact that an HO inhibitor, zinc protoporphyrin, downregulates LPS-mediated HO-1 expression, leading to a further increase in NOS2 expression (Furuichi et al, 2009). Moreover, antiinflammatory and anti-apoptotic responses in p,p -DDT-treated livers suggests the expression of cytoprotective molecules, because such molecules have been previously found to be expressed in the liver of rats treated with various hepatic drug-enzyme inducers (Kobayashi et al, 2000;Reed et al, 2011).…”

Isoflurane post-treatment improves pulmonary vascular permeability via upregulation of heme oxygenase-1

“…The protective role of HO-1 has been demonstrated in experimental lung in LPS and CLP models [21,22]. We found that HO-1 acts as a potent antiinflammatory and antioxidant agent through its products CO and biliverdin.…”

Heme oxygenase 1 improves glucoses metabolism and kidney histological alterations in diabetic rats

“…This effect resulted from oxidative stress inhibition [35]. Additionally, the interaction between heme oxygenase and nitric oxide (NO) has already been observed in the kidney [36]. The HO-1 induction inhibits NO synthase [37], however fewer works have demonstrated the interaction between these systems in the kidneys of diabetic animals.…”