Erica L. Martin1,*, Danielle G. Souza2,*, Caio T. Fagundes2, Flavio A. Amaral2, Barbara Assenzio1, Valeria Puntorieri1, Lorenzo Del Sorbo1, Vito Fanelli1, Martino Bosco3, Luisa Delsedime3, Jose F. Pinho4, Virginia S. Lemos4, Fabricio O. Souto5, Jose C. Alves-Filho5, Fernando Q. Cunha5, Arthur S. Slutsky6, Thomas Ruckle7, Emilio Hirsch8, Mauro M. Teixeira2, and V. Marco Ranieri1. American Journal of Respiratory and Critical Care Medicine Vol 182. pp. 762-773, (2010). Published ahead of print on May 27, 2010, doi:10.1164/rccm.201001-0088OC
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 (PI3K) 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 in the pathogenesis of sepsis and multiorgan damage.
Methods: PI3K 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 inhibitor and assessed for survival, neutrophil recruitment, and bacterial spread.
Measurements and Main Results: Both genetic and pharmaceutical PI3K 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 pharmacological inhibition significantly decreased mortality and improved neutrophil migration and bacterial control, even when administered during established septic shock.
Conclusions: This study establishes PI3K 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.
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