Lung congestion as a hidden threat in end-stage kidney disease: a call to action

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Pulmonary-derived phosphoinositide 3-kinase gamma (PI3K\u3b3) contributes to ventilator-induced lung injury and edema

BACKGROUND: Ventilator-induced lung injury (VILI) occurs in part by increased vascular permeability and impaired alveolar fluid clearance. Phosphoinositide 3-kinase gamma (PI3K\u3b3) is activated by mechanical stress, induces nitric oxide (NO) production, and participates in cyclic adenosine monophosphate (cAMP) hydrolysis, each of which contributes to alveolar edema. We hypothesized that lungs lacking PI3K\u3b3 or treated with PI3K\u3b3 inhibitors would be protected from ventilation-induced alveolar edema and lung injury. METHODS: Using an isolated and perfused lung model, wild-type (WT) and PI3K\u3b3-knockout (KO) mice underwent negative-pressure cycled ventilation at either -25 cmH\u2082O and 0 cmH\u2082O positive end-expiratory pressure (PEEP) (HIGH STRESS) or -10 cmH\u2082O and -3 cmH\u2082O PEEP (LOW STRESS). RESULTS: Compared with WT, PI3K\u3b3-knockout mice lungs were partially protected from VILI-induced derangement of respiratory mechanics (lung elastance) and edema formation [bronchoalveolar lavage (BAL) protein concentration, wet/dry ratio, and lung histology]. In PI3K\u3b3-knockout mice, VILI induced significantly less phosphorylation of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), production of nitrate and nitrotyrosine, as well as hydrolysis of cAMP, compared with wild-type animals. PI3K\u3b3 wild-type lungs treated with AS605240, an inhibitor of PI3K\u3b3 kinase activity, in combination with enoximone, an inhibitor of phosphodiesterase-3 (PDE3)-induced cAMP hydrolysis, were protected from VILI at levels comparable to knockout lungs. CONCLUSIONS: Phosphoinositide 3-kinase gamma in resident lung cells mediates part of the alveolar edema induced by high-stress ventilation. This injury is mediated via altered Akt, eNOS, NO, and/or cAMP signaling. Anti-PI3K\u3b3 therapy aimed at resident lung cells represents a potential pharmacologic target to mitigate VILI

Phosphoinositide-3 kinase gamma activity contributes to sepsis and organ damage by altering neutrophil recruitment

RATIONALE: Sepsis is a leading cause of death in the intensive care unit, characterized by a systemic inflammatory response (SIRS) and bacterial infection, which can often induce multiorgan damage and failure. Leukocyte recruitment, required to limit bacterial spread, depends on phosphoinositide-3 kinase \u3b3 (PI3K\u3b3) signaling in vitro; however, the role of this enzyme in polymicrobial sepsis has remained unclear. OBJECTIVES: This study aimed to determine the specific role of the kinase activity of PI3K\u3b3 in the pathogenesis of sepsis and multiorgan damage. METHODS: PI3K\u3b3 wild-type, knockout, and kinase-dead mice were exposed to cecal ligation and perforation-induced sepsis and assessed for survival; pulmonary, hepatic, and cardiovascular damage; coagulation derangements; systemic inflammation; bacterial spread; and neutrophil recruitment. Additionally, wild-type mice were treated either before or after the onset of sepsis with a PI3K\u3b3 inhibitor and assessed for survival, neutrophil recruitment, and bacterial spread. MEASUREMENTS AND MAIN RESULTS: Both genetic and pharmaceutical PI3K\u3b3 kinase inhibition significantly improved survival, reduced multiorgan damage, and limited bacterial decompartmentalization, while modestly affecting SIRS. Protection resulted from both neutrophil-independent mechanisms, involving improved cardiovascular function, and neutrophil-dependent mechanisms, through reduced susceptibility to neutrophil migration failure during severe sepsis by maintaining neutrophil surface expression of the chemokine receptor, CXCR2. Furthermore, PI3K\u3b3 pharmacological inhibition significantly decreased mortality and improved neutrophil migration and bacterial control, even when administered during established septic shock. CONCLUSIONS: This study establishes PI3K\u3b3 as a key molecule in the pathogenesis of septic infection and the transition from SIRS to organ damage and identifies it as a novel possible therapeutic target