Role of phosphatidylinositol 3-kinase-gamma in mediating lung neutrophil sequestration and vascular injury induced by E. coli sepsis.
We addressed the in vivo role of phosphatidylinositol 3-kinase-gamma (PI3K-gamma) in signaling the sequestration of polymorphonuclear leukocytes (PMNs) in lungs and in the mechanism of inflammatory lung vascular injury. We studied mice with deletion of the p110 catalytic subunit of PI3K-gamma (PI3K-gamma(-/-) mice). We measured lung tissue PMN sequestration, microvascular permeability, and edema formation after bacteremia induced by intraperitoneal Escherichia coli challenge. PMN infiltration into the lung interstitium in PI3K-gamma(-/-) mice as assessed morphometrically was increased 100% over that in control mice within 1 h after bacterial challenge. PI3K-gamma(-/-) mice also developed a greater increase in lung microvascular permeability after E. coli challenge, resulting in edema formation. The augmented lung tissue PMN sequestration in PI3K-gamma(-/-) mice was associated with increased expression of the PMN adhesive proteins CD47 and beta(3)-integrins. We observed increased association of CD47 and beta(3)-integrins with the extracellular matrix protein vitronectin in lungs of PI3K-gamma(-/-) mice after E. coli challenge. PMNs from these mice also showed increased beta(3)-integrin expression and augmented beta(3)-integrin-dependent PMN adhesion to vitronectin. These results point to a key role of PMN PI3K-gamma in negatively regulating CD47 and beta(3)-integrin expression in gram-negative sepsis. PI3K-gamma activation in PMNs induced by E. coli may modulate the extent of lung tissue PMN sequestration secondary to CD47 and beta(3)-integrin expression. Therefore, the level of PI3K-gamma activation may be an important determinant of PMN-dependent lung vascular injury.
Ong
Evan
E
Dept. of Pharmacology, College of Medicine, The University of Illinois, 835 South Wolcott Avenue, Chicago, IL 60612-7343, USA.
Gao
Xiao-Pei
XP
Predescu
Dan
D
Broman
Michael
M
Malik
Asrar B
AB
D000818:Animals; D001808:Blood Vessels / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D001998:Bronchopulmonary Sequestration / Q000201:enzymology / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D051928:CD47 Antigen / Q000378:metabolism; D002199:Capillary Permeability / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D039661:Integrin beta3 / Q000378:metabolism; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics
D051928:CD47 Antigen; D058544:Class Ib Phosphatidylinositol 3-Kinase; D039661:Integrin beta3; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; C497895:Cd47 protein, mouse; C546764:Pik3cg protein, mouse