[The role of hydrogen sulfide in acute lung injury during endotoxic shock and its relationship with nitric oxide and carbon monoxide].
ABSTRACT To explore the role of hydrogen sulfide (H2S) in acute lung injury (ALI) during endotoxic shock (ES) and its relationship with nitric oxide (NO) and carbon monoxide (CO).
Sixty-four adult male SD rats were randomly divided into 4 equal groups: control group injected with normal saline via the caudal vein, lipopolysaccharide (LPS)-treated group injected with LPS to establish ES model, LPS + NaHS group injected with LPS and sodium hydrosulfide (NaHS, an exogenous H2S donor], and LPS + PPG group injected with LPS and polypropylene glycol (PPG, a H2S synthase inhibitor). The mean artery pressure (MAP) was measured via a polyethylene catheter in the right common carotid artery for 6 h. Then the rats were sacrificed with their lungs taken out to determine the lung water content, lung tissue malonyldialdehyde (MDA), NO, and CO contents, as well as lung tissue cystathionine-gamma-lyase (CSE), myeloperoxidase (MPO), nitric oxide synthase (NOS), and heme oxygenase (HO) activities. The H2S content in blood plasma was detected also. Morphological changes of the lung tissues were observed under light microscope and the index of quantitative assessment (IQA) of lung injury was calculated. Immunohistochemistry and Western blotting were used to detect the lung tissue inducible NOS (iNOS) and HO-1 protein expression.
Compared with the control group, the MAP of the LPS group was significantly lower, the pathological changes in lung tissue was more obvious, and the IQA, lung water content, lung MDA content, lung MPO and CSE activities as well as plasma H2S content were all significantly higher (P < 0.05 or P < 0.01). Compared to the LPS group, the plasma H2S and lung CSE activity of the LPS + NaHS group were higher, the lung injury was more severe, and the MAP was lower. And compared to the LPS group, the MAP of the LPS + PPG group was higher, and the lung injury was milder (both P < 0.05). The eNOS activity in the lung tissue of the LPS group was (5.26 +/- 0.25) Uxmg(-1)xprot(-1), significantly lower than that of the control group [(6.45 +/- 0.42) Uxmg(-1)xprot(-1)]; and the iNOS activity and NO content of the LPS group were (12.6 +/- 0.6) Uxmg(-1)xprot(-1) and (144 +/- 25) micromol/L respectively, both higher than those of the control group [(10.5 +/- 0.7) Uxmg(-1)xprot(-1) and (68 +/- 5) micromol/L respectively] (P < 0.05 or P < 0.01). Compared with the LPS group, the lung tissue eNOS activity of the LPS + PPG group was significantly higher, and the iNOS activity [(10.2 +/- 0.4) Uxmg(-1)xprot(-1)], iNOS protein expression, and NO content [(74 +/- 5) micromol/L]were all significantly lower (P < 0.05 or P < 0.01). Compared with the LPS group, the lung tissue eNOS activity of the LPS + NaHS group [(4.81 +/- 0.23) Uxmg(-1)xprot(-1)] was significantly lower, and the iNOS activity [(14.6 +/- 0.4) Uxmg(-1)xprot(-1)], iNOS protein expression, and NO content [(217 +/- 18) micromol/L] were significantly higher (P < 0.05 or P < 0.01). The lung tissue HO activity [(173 +/- 31) pkat/g], HO protein expression, and CO content [(3.63 +/- 0.24)%] of the LPS group were all significantly higher than those of the control group [(125 +/- 22) pkat/g, (2.48 +/- 0.33)%, both P < 0.05], and the LPS + PPG group [(88 +/- 17) pkat/g, (2.98 +/- 0.23)%, both P < 0.05]. Compared to the LPS group, the lung tissue HO activity [(263 +/- 37) pkat/g], HO protein expression, and CO content [(4.35 +/- 0.32)%] of the LPS + NaHS group were all significantly higher (all P < 0.05).
The increase of H(2)S generation participates in the lung tissue injury during ES and this event is related to eNOS activity decrease, iNOS activity increase that causes the production of large amount of NO. H2S up-regulates the HO-1/CO system in the lung tissues during ES, which may be the endogenous compensatory response against the injury.
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ABSTRACT: Hydrogen sulphide (H(2) S) is emerging as an important endogenous modulator, which exhibits the beneficial effects of nitric oxide (NO) on the cardiovascular (CV) system, without producing toxic metabolites. H(2) S is biosynthesized in mammalian tissues by cystathionine-β-synthase and cystathionine-γ-lyase. H(2) S exhibits the antioxidant properties of inorganic and organic sulphites, behaving as a scavenger of reactive oxygen species. There is also clear evidence that H(2) S triggers other important effects, mainly mediated by the activation of ATP-sensitive potassium channels (K(ATP) ). This mechanism accounts for the vasorelaxing and cardioprotective effects of H(2) S. Furthermore, H(2) S inhibits smooth muscle proliferation and platelet aggregation. In non-CV systems, H(2) S regulates the functions of the central nervous system, as well as respiratory, gastroenteric, and endocrine systems. Conversely, H(2) S deficiency contributes to the pathogenesis of hypertension. Likewise, impairment of H(2) S biosynthesis is involved in CV complications associated with diabetes mellitus. There is also evidence of a cross-talk between the H(2) S and the endothelial NO pathways. In particular, recent observations indicate a possible pathogenic link between deficiencies of H(2) S activity and the progress of endothelial dysfunction. These biological aspects of endogenous H(2) S have led several authors to look at this mediator as "the new NO" that has given attractive opportunities to develop innovative classes of drugs. In this review, the main biological actions of H(2) S are discussed. Moreover, some examples of H(2) S-donors are shown, as well as some hybrids, in which H(2) S-releasing moieties are added to well-known drugs, for improving their pharmacodynamic profile or reducing the potential for adverse effects, are reported.Medicinal Research Reviews 11/2012; 32(6):1093-130. · 10.70 Impact Factor