Treatment of ARDS With Prone Positioning

Prone positioning was first proposed in the 1970s as a method to improve gas exchange in ARDS. Subsequent observations of dramatic improvement in oxygenation with simple patient rotation motivated the next several decades of research. This work elucidated the physiological mechanisms underlying changes in gas exchange and respiratory mechanics with prone ventilation. However, translating physiological improvements into a clinical benefit has proved challenging; several contemporary trials showed no major clinical benefits with prone positioning. By optimizing patient selection and treatment protocols, the recent Proning Severe ARDS Patients (PROSEVA) trial demonstrated a significant mortality benefit with prone ventilation. This trial, and subsequent meta-analyses, support the role of prone positioning as an effective therapy to reduce mortality in severe ARDS, particularly when applied early with other lung-protective strategies. This review discusses the physiological principles, clinical evidence, and practical application of prone ventilation in ARDS

Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis

Background: The beneficial outcome associated with the use of proton pump inhibitors (PPIs) in idiopathic pulmonary fibrosis (IPF) has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in IPF has not been elucidated. Methods: Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with inflammation and fibrosis. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce inflammation and fibrosis. In addition, we cultured lung fibroblasts from IPF patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease (ILD) databases to examine the effect of PPIs on transplant-free survival. Results: The cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF-alpha) and interleukins (IL-1 beta and IL-6). The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 (HO1) and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor beta (TGF beta), fibronectin and matrix metalloproteinases (MMPs). Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in IPF patients. Intriguingly, this data demonstrated that IPF patients on PPIs had prolonged survival over controls (median survival of 3.4 vs 2 years). Conclusions: Overall, these data indicate the possibility that PPIs may have protective function in IPF by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.Stanford School of Medicine [1049528-149- KAVFB]; Tobacco-Related Disease Research Program of the University of California [20FT-0090]; National Institutes of Health National Heart, Lung, and Blood Institute [5K01HL118683, P01HL114470]; Houston Methodist Research Institute [25150001]; Stanford SPARK Translational Research ProgramSCI(E)[email protected]

Metabolomic changes in murine serum following inhalation exposure to gasoline and diesel engine emissions

The adverse health effects of environmental exposure to gaseous and particulate components of vehicular emissions are a major concern among urban populations. A link has been established between respiratory exposure to vehicular emissions and the development of cardiovascular disease (CVD), but the mechanisms driving this interaction remain unknown. Chronic inhalation exposure to mixed vehicle emissions has been linked to CVD in animal models. This study evaluated the temporal effects of acute exposure to mixed vehicle emissions (MVE; mixed gasoline and diesel emissions) on potentially active metabolites in the serum of exposed mice. C57Bl/6 mice were exposed to a single 6-hour exposure to filtered air (FA) or MVE (100 or 300 μg/m(3)) by whole body inhalation. Immediately after and 18 hours after the end of the exposure period, animals were sacrificed for serum and tissue collection. Serum was analyzed for metabolites that were differentially present between treatment groups and time points. Changes in metabolite levels suggestive of increased oxidative stress (oxidized glutathione, cysteine disulfide, taurine), lipid peroxidation (13-HODE, 9-HODE), energy metabolism (lactate, glycerate, branched chain amino acid catabolites, butrylcarnitine, fatty acids), and inflammation (DiHOME, palmitoyl ethanolamide) were observed immediately after the end of exposure in the serum of animals exposed to MVE relative to those exposed to FA. By 18 hours post exposure, serum metabolite differences between animals exposed to MVE versus those exposed to FA were less pronounced. These findings highlight complex metabolomics alterations in the circulation following inhalation exposure to a common source of combustion emissions

Metabolomic changes in murine serum following inhalation exposure to gasoline and diesel engine emissions

The adverse health effects of environmental exposure to gaseous and particulate components of vehicular emissions are a major concern among urban populations. A link has been established between respiratory exposure to vehicular emissions and the development of cardiovascular disease (CVD), but the mechanisms driving this interaction remain unknown. Chronic inhalation exposure to mixed vehicle emissions has been linked to CVD in animal models. This study evaluated the temporal effects of acute exposure to mixed vehicle emissions (MVE; mixed gasoline and diesel emissions) on potentially active metabolites in the serum of exposed mice. C57Bl/6 mice were exposed to a single 6 hour exposure to filtered air (FA) or MVE (100 or 300 µg/m(3)) by whole body inhalation. Immediately after and 18 hours after the end of the exposure period, animals were sacrificed for serum and tissue collection. Serum was analyzed for metabolites that were differentially present between treatment groups and time points. Changes in metabolite levels suggestive of increased oxidative stress (oxidized glutathione, cysteine disulfide, taurine), lipid peroxidation (13-HODE, 9-HODE), energy metabolism (lactate, glycerate, branched chain amino acid catabolites, butrylcarnitine, fatty acids), and inflammation (DiHOME, palmitoyl ethanolamide) were observed immediately after the end of exposure in the serum of animals exposed to MVE relative to those exposed to FA. By 18 hours post exposure, serum metabolite differences between animals exposed to MVE versus those exposed to FA were less pronounced. These findings highlight complex metabolomics alterations in the circulation following inhalation exposure to a common source of combustion emissions