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Phosphoinositide-3 kinase gamma kinase activity significantly contributes to the pathophysiology of sepsis and multiorgan failure
Critical Care volume 12, Article number: P39 (2008)
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.
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.
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.
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.
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Martin, E., Bosco, M., Delsedime, L. et al. Phosphoinositide-3 kinase gamma kinase activity significantly contributes to the pathophysiology of sepsis and multiorgan failure. Crit Care 12, P39 (2008). https://doi.org/10.1186/cc7072
- Systemic Inflammatory Response Syndrome
- Multiple Organ Failure
- Multiorgan Failure
- Leukocyte Infiltration
- Leukocyte Recruitment