Role of phosphatidylinositol 3-kinase-gamma in mediating lung neutrophil sequestration and vascular injury induced by E. coli sepsis

Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L1094-103. doi: 10.1152/ajplung.00179.2005. Epub 2005 Sep 23.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Vessels / enzymology
  • Blood Vessels / injuries
  • Blood Vessels / pathology
  • Bronchopulmonary Sequestration / enzymology
  • Bronchopulmonary Sequestration / genetics
  • Bronchopulmonary Sequestration / microbiology
  • Bronchopulmonary Sequestration / pathology
  • CD47 Antigen / metabolism
  • Capillary Permeability / genetics
  • Cell Adhesion / genetics
  • Class Ib Phosphatidylinositol 3-Kinase
  • Escherichia coli Infections / complications
  • Escherichia coli Infections / enzymology*
  • Escherichia coli Infections / genetics
  • Escherichia coli Infections / pathology
  • Escherichia coli*
  • Gene Expression Regulation / genetics
  • Integrin beta3 / metabolism
  • Isoenzymes / deficiency
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Lung / enzymology
  • Lung / microbiology
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration* / genetics
  • Neutrophils / enzymology*
  • Neutrophils / pathology
  • Phosphatidylinositol 3-Kinases / deficiency
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Sepsis / enzymology*
  • Sepsis / genetics
  • Sepsis / microbiology
  • Sepsis / pathology
  • Signal Transduction / genetics

Substances

  • CD47 Antigen
  • Cd47 protein, mouse
  • Integrin beta3
  • Isoenzymes
  • Class Ib Phosphatidylinositol 3-Kinase
  • Pik3cg protein, mouse