Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung.
In models of acute lung injury, CXC chemokine receptor 2 (CXCR2) mediates migration of polymorphonuclear leukocytes (PMNs) into the lung. Since CXCR2 ligands, including CXCL1 and CXCL2/3, are chemotactic for PMNs, CXCR2 is thought to recruit PMNs by inducing chemotactic migration. In a model of PMN recruitment to the lung, aerosolized bacterial LPS inhalation induced PMN recruitment to the lung in wild-type mice, but not in littermate CXCR2-/- mice. Surprisingly, lethally irradiated wild-type mice reconstituted with CXCR2-/- BM still showed about 50% PMN recruitment into bronchoalveolar lavage fluid and into lung interstitium, but CXCR2-/- mice reconstituted with CXCR2-/- BM showed no PMN recruitment. Conversely, CXCR2-/- mice reconstituted with wild-type BM showed a surprisingly large defect in PMN recruitment, inconsistent with a role of CXCR2 on PMNs alone. Cell culture, immunohistochemistry, flow cytometry, and real-time RT-PCR were used to show expression of CXCR2 on pulmonary endothelial and bronchial epithelial cells. The LPS-induced increase in lung microvascular permeability as measured by Evans blue extravasation required CXCR2 on nonhematopoietic cells. Our data revealed what we believe to be a previously unrecognized role of endothelial and epithelial CXCR2 in LPS-induced PMN recruitment and lung injury.
Reutershan
Jörg
J
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908-1394, USA.
Morris
Margaret A
MA
Burcin
Tracy L
TL
Smith
David F
DF
Chang
Daniel
D
Saprito
Mary S
MS
Ley
Klaus
K
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000098:blood supply / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D011828:Radiation Chimera; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B