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Alveolar fluid clearance in acute lung injury: what have we learned from animal models and clinical studies?

ABSTRACT: BACKGROUND:Acute lung injury and the acute respiratory distress syndrome continue to be significant causes of morbidity and mortality in the intensive care setting. The failure of patients to resolve the alveolar edema associated with these conditions is a major contributing factor to mortality; hence there is continued interest to understand the mechanisms of alveolar edema fluid clearance. DISCUSSION:The accompanying review by Vadász et al. details our current understanding of the signaling mechanisms and cellular processes that facilitate clearance of edema fluid from the alveolar compartment, and how these signaling processes may be exploited in the development of novel therapeutic strategies. To complement that report this review focuses on how intact organ and animal models and clinical studies have facilitated our understanding of alveolar edema fluid clearance in acute lung injury and acute respiratory distress syndrome. Furthermore, it considers how what we have learned from these animal and organ models and clinical studies has suggested novel therapeutic avenues to pursue.

SUBMITTER: Morty RE

PROVIDER: S-EPMC7095514 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Alveolar fluid clearance in acute lung injury: what have we learned from animal models and clinical studies?

Morty Rory E RE Eickelberg Oliver O Seeger Werner W

Intensive care medicine 20070525 7

<h4>Background</h4>Acute lung injury and the acute respiratory distress syndrome continue to be significant causes of morbidity and mortality in the intensive care setting. The failure of patients to resolve the alveolar edema associated with these conditions is a major contributing factor to mortality; hence there is continued interest to understand the mechanisms of alveolar edema fluid clearance.<h4>Discussion</h4>The accompanying review by Vadász et al. details our current understanding of t ...[more]

PMID: 17525842

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Project description:BackgroundPulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS). The epithelial sodium channel (ENaC) is thought to be the rate-limiting factor for alveolar fluid clearance (AFC) during pulmonary edema. The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone was shown to stimulate ENaC-mediated salt absorption in the kidney. However, its role in the lung remains unclear. Here, we investigated the role of the PPARγ agonist in the lung to find out whether it can regulate AFC during acute lung injury (ALI). We also attempted to elucidate the mechanism for this.MethodsOur ALI model was established through intratracheal instillation of lipopolysaccharide (LPS) in C57BL/6 J mice. The mice were randomly divided into 4 groups of 10. The control group underwent a sham operation and received an equal quantity of saline. The three experimental groups underwent intratracheal instillation of 5 mg/kg LPS, followed by intraperitoneal injection of 4 mg/kg rosiglitazone, 4 mg/kg rosiglitazone plus 1 mg/kg GW9662, or only equal quantity of saline. The histological morphology of the lung, the levels of TNF-α and IL-1β in the bronchoalveolar lavage fluid (BALF), the level of AFC, and the expressions of αENaC and serum and glucocorticoid-induced kinase-1 (SGK1) were determined. Type 2 alveolar (AT II) cells were incubated with rosiglitazone (15 μM) with or without GW9662 (10 μM). The expressions of αENaC and SGK1 were determined 24 h later.ResultsA mouse model of ALI was successfully established. Rosiglitazone significantly ameliorated the lung injury, decreasing the TNF-α and IL-1β levels in the BALF, enhancing AFC, and promoting the expressions of αENaC and SGK1 in ALI mice, which were abolished by the specific PPARγ blocker GW9662. In vitro, rosiglitazone increased the expressions of αENaC and SGK1. This increase was prevented by GW9662.ConclusionsRosiglitazone ameliorated the lung injury and promoted ENaC-mediated AFC via a PPARγ/SGK1-dependent signaling pathway, alleviating pulmonary edema in a mouse model of ALI.

Project description:Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is characterized by diffuse alveolar damage and significant edema accumulation, which is associated with impaired alveolar fluid clearance (AFC) and alveolar-capillary barrier disruption, leading to acute respiratory failure. Our previous data showed that electroporation-mediated gene delivery of the Na+, K+-ATPase β1 subunit not only increased AFC, but also restored alveolar barrier function through upregulation of tight junction proteins, leading to treatment of LPS-induced ALI in mice. More importantly, our recent publication showed that gene delivery of MRCKα, the downstream effector of β1 subunit-mediated signaling towards upregulation of adhesive junctions and epithelial and endothelial barrier integrity, also provided therapeutic potential for ARDS treatment in vivo but without necessarily accelerating AFC, indicating that for ARDS treatment, improving alveolar capillary barrier function may be of more benefit than improving fluid clearance. In the present study, we investigated the therapeutical potential of β2 and β3 subunits, the other two β isoforms of Na+, K+-ATPase, for LPS-induced ALI. We found that gene transfer of either the β1, β2, or β3 subunits significantly increased AFC compared to the basal level in naïve animals and each gave similar increased AFC to each other. However, unlike that of the β1 subunit, gene transfer of the β2 or β3 subunit into pre-injured animal lungs failed to show the beneficial effects of attenuated histological damage, neutrophil infiltration, overall lung edema, or increased lung permeability, indicating that β2 or β3 gene delivery could not treat LPS induced lung injury. Further, while β1 gene transfer increased levels of key tight junction proteins in the lungs of injured mice, that of either the β2 or β3 subunit had no effect on levels of tight junction proteins. Taken together, this strongly suggests that restoration of alveolar-capillary barrier function alone may be of equal or even more benefit than improving AFC for ALI/ARDS treatment.

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Alveolar fluid clearance in acute lung injury: what have we learned from animal models and clinical studies?

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Alveolar fluid clearance in acute lung injury: what have we learned from animal models and clinical studies?

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