Disruption of Platelet-derived Chemokine Heteromers Prevents Neutrophil Extravasation in Acute Lung Injury

Jochen Grommes, Jean-Eric Alard, Maik Drechsler, Sarawuth Wantha, Matthias Morgelin, Wolfgang M. Kuebler, Michael Jacobs, Philipp von Hundelshausen, Philipp Markart, Malgorzata Wygrecka, Klaus T. Preissner, Tilman M. Hackeng, Rory R. Koenen, Christian Weber, Oliver Soehnlein*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

158 Citations (Web of Science)

Abstract

Rationale: 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. Objectives: 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. Measurements and Main 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.
Original languageEnglish
Pages (from-to)628-636
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume185
Issue number6
DOIs
Publication statusPublished - 15 Mar 2012

Keywords

  • neutrophil
  • platelet
  • chemokine
  • recruitment
  • acute lung injury

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