Protective Effects of Pravastatin in Murine Lipopolysaccharide‐induced Acute Lung Injury

Abstract

1. The present study was designed to determine whether pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, could attenuate acute lung injury (ALI) induced by lipopolysaccharide (LPS) in BALB/c mice. 2. Acute lung injury was induced successfully by intratracheal administraiton of LPS (3 microg/g) in BALB/c mice. Pravastatin (3, 10 and 30 mg/kg, i.p.) was administered to mice 24 h prior to and then again concomitant with LPS exposure. 3. Challenge with LPS alone produced a significant increase in lung index and the wet/dry weight ratio compared with control animals. Pulmonary microvascular leakage, as indicated by albumin content in the bronchoalveolar lavage fluid (BALF) and extravasation of Evans blue dye albumin into lung tissue, was apparently increased in LPS-exposed mice. Lipopolysaccharide exposure also produced a significant lung inflammatory response, reflected by myeloperoxidase activity and inflammatory cell counts in BALF. Furthermore, histological examination showed that mice exposed to LPS also exhibited prominent inflammatory cell infiltration and occasional alveolar haemorrhage. 4. Pravastatin (3, 10 or 30 mg/kg, i.p.) produced a significant reduction in multiple indices of LPS-induced pulmonary vascular leak and inflammatory cell infiltration into lung tissue. Elevated tumour necrosis factor (TNF)-alpha levels in lung tissue homogenates of ALI mice were significantly decreased after administration of 10 or 30 mg/kg pravastatin. 5. These findings confirm significant protection by pravastatin against LPS-induced lung vascular leak and inflammation and implicate a potential role for statins in the management of ALI. The inhibitory effect of pravastatin was associated with its effect in decreasing TNF-alpha.

Successful Treatment of Acute Lung Injury with Pitavastatin in Septic Mice: Potential Role of Glucocorticoid Receptor Expression in Alveolar Macrophages

“…at ASPET Journals on May 10, 2018 jpet.aspetjournals.org tin, suggesting that the inhibition of ALI by pitavastatin may be associated with its decreasing effect on TNF-␣ (Yao et al, 2006). Likewise, the ability of pitavastatin to mitigate the increases in circulating levels of TNF-␣ and IL-6 after CLPinduced sepsis was demonstrated in this study.…”

“…The data are in good agreement with those obtained with other statins in LPS-challenged mice. Thus, simvastatin and pravastatin have been shown to significantly decrease intratracheal LPS-induced murine lung vascular leak and inflammation (Jacobson et al, 2005;Yao et al, 2006). Taken together, these results would implicate the potential for the class of drugs known as statins to serve as a novel therapeutic tool in ALI.…”

Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy Volunteers

“…This is the first study to find this effect in the pulmonary compartment in humans, although previous animal studies have demonstrated that statins attenuate TNF-a release in BALF after intratracheal administration of LPS in mice (44). TNF-a is characteristically induced in, and secreted by, LPSstimulated alveolar macrophages (33,35) and is NF-kB-dependent (45).…”

Mechanisms of Neutrophil Accumulation in the Lungs Against Bacteria

“…Conversely, the potential for therapies that reduce cellular and serum cholesterol to reduce PMN recruitment to the airspace has also been reported. Three different hydroxy-methylglutaryl coenzyme A reductase inhibitors (''statins'') used to treat clinical hypercholesterolemia have now been shown to reduce PMN recruitment to and microvas-cular injury within the rodent lung following LPS exposure (80)(81)(82), likely due to dual effects upon PMN chemotaxis and endothelium. Statins also enhance clearance of apoptotic PMNs by alveolar macrophages (83).…”