Phosphoinositide-3 kinase gamma kinase activity significantly contributes to the pathophysiology of sepsis and multiorgan failure

Background

Sepsis is characterized by systemic inflammation (systemic inflammatory response syndrome (SIRS)), leading to multiple organ failure and death. The lung and liver are both prone to septic-induced damage resulting from leukocyte infiltration, cellular apoptosis, and epithelial/endothelial breakdown. Furthermore, coagulation can potentiate the inflammatory response and contribute to septic mortality. Phosphoinositide-3 kinase gamma (PI3Kγ) plays a dominant role in the inflammatory response; however, its role in the pathogenesis of sepsis, specifically SIRS, lung/liver inflammation and damage, apoptosis, coagulation and mortality remains unknown. We hypothesized that mice lacking PI3Kγ or possessing a kinase-dead enzyme will be protected against septic-induced injury.

Methods

PI3Kγ wild-type (WT), knockout (KO) and kinase dead (KD) mice were randomized to cecal ligation and perforation (CLP)-induced sepsis or a sham laporatomy. After 18 hours, plasma and bronchoalveolar lavage and/or lung and liver tissue were collected. Plasma was assessed for inflammatory mediators and the lung/liver was analysed for pathology score, leukocyte infiltration, inflammatory mediators, edema, apoptosis, coagulation and downstream intracellular signalling of PI3Kγ. A separate cohort of WT and KO mice were used for evaluation of 7-day survival following CLP.

Results

Systemically, KO and KD mice showed a reduction in five of 22 measured cytokines/chemokines (MIP1a, MIP2, RANTES, MCP1 and IL-10) compared with WT controls. In the lungs, KO and KD mice were significantly protected against septic damage, as observed by decreased pathology scores, edema/permeability, leukocyte infiltration, inflammation (all 22 measured mediators), apoptosis and Akt/mitogen-activated protein kinase activation, compared with WT lungs. Similarly, livers of CLP-exposed KO and KD mice had decreased pathology scores, leukocyte infiltration, apoptosis and coagulation derangements compared with WT controls. Furthermore, Kaplan–Meier analysis of 7-day survival following CLP showed KO mice had significantly reduced mortality compared with WT mice. See Table 1.

Table 1 Portion of results displaying the systemic, lung, liver and coagulation responses of PI3KγWT, KO and KD mice to CLP-induced sepsis

Conclusion

The present study demonstrates that while PI3Kγ has a modest effect on SIRS during sepsis, its kinase activity is pivotal to the successive development of coagulation derangement and lung/liver inflammation and damage, probably through the modification of leukocyte recruitment and apoptosis. Furthermore, PI3Kγ is shown to effect CLP-septic-induced mortality, implying that it may be a possible therapeutic target in sepsis and multiple organ failure.