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Disruption of Platelet-derived Chemokine Heteromers Prevents Neutrophil Extravasation in Acute Lung Injury
- Source :
- American Journal of Respiratory and Critical Care Medicine, 185(6), 628-636. American Thoracic Society, American Journal of Respiratory and Critical Care Medicine
- Publication Year :
- 2012
- Publisher :
- American Thoracic Society, 2012.
-
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.
- Subjects :
- Pulmonary and Respiratory Medicine
Male
Chemokine
Neutrophils
animal diseases
Vascular permeability
Lung injury
Critical Care and Intensive Care Medicine
Platelet Factor 4
Capillary Permeability
Mice
Cell Movement
Correspondence
medicine
Animals
Humans
Platelet
Platelet activation
Chemokine CCL5
Lung
platelet
Neutrophil extravasation
biology
business.industry
chemokine
neutrophil
Articles
respiratory system
medicine.disease
Platelet Activation
respiratory tract diseases
Mice, Inbred C57BL
Disease Models, Animal
recruitment
acute lung injury
Immunology
biology.protein
Microscopy, Electron, Scanning
business
Infiltration (medical)
Platelet factor 4
Subjects
Details
- Language :
- English
- ISSN :
- 15354970 and 1073449X
- Volume :
- 185
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- American Journal of Respiratory and Critical Care Medicine
- Accession number :
- edsair.doi.dedup.....dc54511d27a2d44c1ab4cf96b5bfe7e0