Pharmacotherapy of acute lung injury and acute respiratory distress syndrome.
ABSTRACT Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article.
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ABSTRACT: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality, and have no specific therapy. Keratinocyte growth factor (KGF) is a critical factor for pulmonary epithelial repair and acts via the stimulation of epithelial cell proliferation. Mesenchymal stem cells (MSCs) have been proved as good therapeutic vectors. Thus, we hypothesized that MSC-based KGF gene therapy would have beneficial effects on lipopolysaccharide(LPS)-induced lung injury. After two hours of intratracheal LPS administration to induce lung injury, mice received saline, MSCs alone, empty vector-engineered MSCs (MSCs-vec) or KGF-engineered MSCs (MSCs-kgf) via the tail vein. The MSCs-kgf could be detected in the recipient lungs and the level of KGF expression significantly increased in the MSCs-kgf mice. The MSC-mediated administration of KGF not only improved pulmonary microvascular permeability but also mediated a down-regulation of proinflammatory responses (reducing IL-1β and TNF-α) and an up-regulation of anti-inflammatory responses (increasing cytokine IL-10). Furthermore, the total severity scores of lung injury were significantly reduced in the MSCs-kgf group compared with the other three groups. The underlying mechanism of the protective effect of KGF on ALI may be attributed to the promotion of type II lung epithelial cell proliferation and the enhancement of surfactant synthesis. These findings suggest that MSCs-based KGF gene therapy may be a promising strategy for ALI treatment.PLoS ONE 12/2013; 8(12):e83303. · 3.53 Impact Factor
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ABSTRACT: Both parenteral and enteral glutamine have shown beneficial effects in sepsis and ischemia/reperfusion-induced acute lung injury (ALI). Oleic acid (OA) has been used to induce ALI in experimental studies. In this study, we investigated the effects of pretreatment of a bolus dose of enteral glutamine on ALI induced by OA in rats. Twenty-eight adult female Sprague-Dawley rats weighing 240-300 g were divided into four groups, 7 in each. Group I and group II received normal saline for 30 days, group III and group IV received glutamine at a dose of 1 g/kg for 10 days by gavage, and in group II and group IV 100 mg/kg OA was administered i.v. Histopathological examination of the lung was performed with light and electron microscopy. Levels of protein carbonyl, malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase levels were measured in tissue samples. Levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and total tissue oxidant status and total tissue antioxidant status were measured in serum samples. Light microscopy showed that the total lung injury score of group IV was significantly lower than group II. Change in thickness of the fused basal lamina was not significantly different in groups II and IV under electron microscopy. TNF-α, IL-6, and IL-10 serum levels were higher in group II when compared to group I and significantly attenuated in group IV. Pretreatment with a bolus dose of enteral glutamine minimized the extent of ALI induced by OA in rats.Journal of Anesthesia 11/2013; 28(3). · 1.12 Impact Factor
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ABSTRACT: The aim of this study was to examine whether dexmedetomidine improves acute liver injury in a rat model. Twenty-eight male Wistar albino rats weighing 300-350 g were allocated randomly to four groups. In group 1, normal saline (NS) was injected into the lungs and rats were allowed to breathe spontaneously. In group 2, rats received standard ventilation (SV) in addition to NS. In group 3, hydrochloric acid was injected into the lungs and rats received SV. In group 4, rats received SV and 100 µg/kg intraperitoneal dexmedetomidine before intratracheal HCl instillation. Blood samples and liver tissue specimens were examined by biochemical, histopathological, and immunohistochemical methods. Acute lung injury (ALI) was found to be associated with increased malondialdehyde (MDA), total oxidant activity (TOA), oxidative stress index (OSI), and decreased total antioxidant capacity (TAC). Significantly decreased MDA, TOA, and OSI levels and significantly increased TAC levels were found with dexmedetomidine injection in group 4 (P < 0.05). The highest histologic injury scores were detected in group 3. Enhanced hepatic vascular endothelial growth factor (VEGF) expression and reduced CD68 expression were found in dexmedetomidine group compared with the group 3. In conclusion, the presented data provide the first evidence that dexmedetomidine has a protective effect on experimental liver injury induced by ALI.BioMed Research International 01/2014; 2014:621827. · 2.71 Impact Factor