title: Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury.
abstract: BACKGROUND
  Acute lung injury (ALI) causes high mortality, but its molecular mechanisms and therapeutic options remain ill-defined. Gram-negative bacterial infections are the main cause of ALI, leading to lung neutrophil infiltration, permeability increases, deterioration of gas exchange, and lung damage. Platelets are activated during ALI, but insights into their mechanistic contribution to neutrophil accumulation in the lung are elusive.
  
  
  OBJECTIVE
  To determine mechanisms of platelet-mediated neutrophil recruitment in ALI.
  
  
  METHODS
  Interference with platelet-neutrophil interactions using antagonists to P-selectin and glycoprotein IIb/IIIa or a small peptide antagonist disrupting platelet chemokine heteromer formation in mouse models of ALI.
  
  
  RESULTS
  In a murine model of LPS-induced ALI, we uncover important roles for neutrophils and platelets in permeability changes and subsequent lung damage. Furthermore, platelet depletion abrogated lung neutrophil infiltration, suggesting a sequential participation of platelets and neutrophils. Whereas antagonists to P-selectin and glycoprotein IIb/IIIa had no effects on LPS-mediated ALI, antibodies to the platelet-derived chemokines CCL5 and CXCL4 strongly diminished neutrophil eflux and permeability changes. The two chemokines were found to form heteromers in human and murine ALI samples, positively correlating with leukocyte influx into the lung. Disruption of CCL5-CXCL4 heteromers in LPS-, acid-, and sepsis-induced ALI abolished lung edema, neutrophil infiltration, and tissue damage, thereby revealing a causal contribution.
  
  
  CONCLUSIONS
  Taken together, our data identify a novel function of platelet-derived chemokine heteromers during ALI and demonstrate means for therapeutic interference.
authors.affiliation: Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Grommes
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Alard
authors.forename: Maik
authors.initials: M
authors.lastname: Drechsler
authors.forename: Sarawuth
authors.initials: S
authors.lastname: Wantha
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.forename: Michael
authors.initials: M
authors.lastname: Jacobs
authors.forename: Philipp
authors.initials: P
authors.lastname: von Hundelshausen
authors.forename: Philipp
authors.initials: P
authors.lastname: Markart
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
authors.forename: Rory R
authors.initials: RR
authors.lastname: Koenen
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002199:Capillary Permeability; D002465:Cell Movement; D018946:Chemokine CCL5 / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D015539:Platelet Activation; D010978:Platelet Factor 4 / Q000378:metabolism*
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D010978:Platelet Factor 4