Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Hemorrhagic shock (HS) elicits an inflammatory response characterized by increased cytokine production and recruitment of PMN which we previously found to be iNOS dependent. In this study we attempted to remove excess induced-NO by administration of the NO scavenger, NOX, with the goal of suppressing proinflammatory signaling and reducing organ damage. Rats subjected to HS (MAP = 40 mmHg for 100 min) followed by resuscitation and examined 24 h later demonstrated histological signs of lung injury including pulmonary edema as well as an 8.6-fold increase in MPO-positive PMN. ⋯ Administration of NOX (30 mg/kg/h beginning at 60 min of shock for total of 4.5 h) resulted in reduced lung injury as measured by a 46% reduction in PMN infiltration, a 20% decrease in wet-to-dry ratio, and improved arterial blood gases. NOX reduced proinflammatory signaling in the lung as demonstrated by a 62% decrease in NF-kappaB binding, 47% reduction in Stat3 binding, a reduction in mRNA expression of 48% for IL-6, 57% for ICAM-1, 67% for IL-1beta, and 64% for TNFalpha, as well as a marked reduction in the intensity of IL-6 protein staining. These data indicate that NOX prevents lung injury in this HS model, possibly through downmodulation of proinflammatory signaling and the shock-induced inflammatory response.
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Sesquiterpene lactones are extracts of common medicinal Asteracae plants used in folk medicine for their anti-inflammatory activity. Recently, in vitro studies have shown that these compounds may interfere with pro-inflammatory gene regulation. This study examines the effects of parthenolide, a sesquiterpene lactone, in experimental myocardial ischemia and reperfusion. ⋯ Administration of parthenolide ameliorated myocardial injury, lowered serum creatine phosphokinase activity, and reduced neutrophil infiltration and the subsequent oxidative damage. These beneficial effects were associated with inhibition of IKK activity, enhanced stability of IkappaBalpha, and inhibition of nuclear translocation of NF-kappaB. The results of this study suggest that parthenolide may be beneficial for the treatment of reperfusion-induced myocardial damage by inhibition of the IKK/NF-kappaB pathway.