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

Grommes, Jochen; Alard, Jean-Eric; Drechsler, Maik; Wantha, Sarawuth; Mörgelin, Matthias LU ; Kuebler, Wolfgang M.; Jacobs, Michael; von Hundelshausen, Philipp; Markart, Philipp and Wygrecka, Malgorzata, et al. (2012) In American Journal of Respiratory and Critical Care Medicine 185(6). p.628-636
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... (More)
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. (Less)
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publication status
published
subject
keywords
acute lung injury, chemokine, recruitment, platelet, neutrophil
in
American Journal of Respiratory and Critical Care Medicine
volume
185
issue
6
pages
628 - 636
publisher
Am Thoracic Soc
external identifiers
  • wos:000301674900009
  • scopus:84858206051
ISSN
1535-4970
DOI
10.1164/rccm.201108-1533OC
language
English
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yes
id
81ce6ed0-58f7-49d4-a4e0-9070d57e7eb7 (old id 2504126)
date added to LUP
2012-05-07 14:08:25
date last changed
2017-11-12 03:00:27
@article{81ce6ed0-58f7-49d4-a4e0-9070d57e7eb7,
  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.},
  author       = {Grommes, Jochen and Alard, Jean-Eric and Drechsler, Maik and Wantha, Sarawuth and Mörgelin, Matthias and Kuebler, Wolfgang M. and Jacobs, Michael and von Hundelshausen, Philipp and Markart, Philipp and Wygrecka, Malgorzata and Preissner, Klaus T. and Hackeng, Tilman M. and Koenen, Rory R. and Weber, Christian and Soehnlein, Oliver},
  issn         = {1535-4970},
  keyword      = {acute lung injury,chemokine,recruitment,platelet,neutrophil},
  language     = {eng},
  number       = {6},
  pages        = {628--636},
  publisher    = {Am Thoracic Soc},
  series       = {American Journal of Respiratory and Critical Care Medicine},
  title        = {Disruption of Platelet-derived Chemokine Heteromers Prevents Neutrophil Extravasation in Acute Lung Injury},
  url          = {http://dx.doi.org/10.1164/rccm.201108-1533OC},
  volume       = {185},
  year         = {2012},
}