Phosphoinositide-3 kinase gamma activity contributes to sepsis and organ damage by altering neutrophil recruitment.
BACKGROUND
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 γ (PI3Kγ) signaling in vitro; however, the role of this enzyme in polymicrobial sepsis has remained unclear.


OBJECTIVE
This study aimed to determine the specific role of the kinase activity of PI3Kγ in the pathogenesis of sepsis and multiorgan damage.


METHODS
PI3Kγ 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 PI3Kγ inhibitor and assessed for survival, neutrophil recruitment, and bacterial spread.


RESULTS
Both genetic and pharmaceutical PI3Kγ 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, PI3Kγ pharmacological inhibition significantly decreased mortality and improved neutrophil migration and bacterial control, even when administered during established septic shock.


CONCLUSIONS
This study establishes PI3Kγ 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.
Martin
Erica L
EL
Department of Anesthesiology and Critical Care, University of Turin, Ospedale S. Giovanni Battista-Molinette, Turin, Italy. ericaleanne.martin@unito.it
Souza
Danielle G
DG
Fagundes
Caio T
CT
Amaral
Flavio A
FA
Assenzio
Barbara
B
Puntorieri
Valeria
V
Del Sorbo
Lorenzo
L
Fanelli
Vito
V
Bosco
Martino
M
Delsedime
Luisa
L
Pinho
Jose F
JF
Lemos
Virginia S
VS
Souto
Fabricio O
FO
Alves-Filho
Jose C
JC
Cunha
Fernando Q
FQ
Slutsky
Arthur S
AS
Ruckle
Thomas
T
Hirsch
Emilio
E
Teixeira
Mauro M
MM
Ranieri
V Marco
VM
D000818:Animals; D002634:Chemotaxis, Leukocyte; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000201:enzymology* / Q000517:prevention & control; D020556:Neutrophil Infiltration / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018805:Sepsis / Q000201:enzymology* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D018746:Systemic Inflammatory Response Syndrome / Q000201:enzymology / Q000517:prevention & control
D058544:Class Ib Phosphatidylinositol 3-Kinase; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C546764:Pik3cg protein, mouse