title: Proteinase-activated receptor-1, CCL2, and CCL7 regulate acute neutrophilic lung inflammation.
abstract: PAR1 plays a central role in mediating the interplay between coagulation and inflammation, but its role in regulating acute neutrophilic inflammation is unknown. We report that antagonism of PAR1 was highly effective at reducing acute neutrophil accumulation in a mouse model of LPS-induced lung inflammation. PAR1 antagonism also reduced alveolar-capillary barrier disruption in these mice. This protection was associated with a reduction in the expression of the chemokines, CCL2 and CCL7, but not the proinflammatory cytokines, TNF and IL-6, or the classic neutrophil chemoattractants, CXCL1 and CXCL2. Antibody neutralization of CCL2 and CCL7 significantly reduced LPS-induced total leukocyte and neutrophil accumulation, recovered from the bronchoalveolar lavage fluid of challenged mice. Immunohistochemical analysis revealed that CCL2 predominantly localized to alveolar macrophages and pulmonary epithelial cells, whereas CCL7 was restricted to the pulmonary epithelium. In keeping with these observations, the intranasal administration of recombinant CCL2 (rCCL2) and rCCL7 led to the accumulation of neutrophils within the lung airspaces of naive mice in the absence of any underlying inflammation. Flow cytometry analysis further demonstrated an increase in Ly6G(hi) neutrophils expressing the chemokine receptors, CCR1 and CCR2, isolated from mouse lungs compared with circulating neutrophils. Conversely, the expression of CXCR2 decreased on neutrophils isolated from the lung compared with circulating neutrophils. Furthermore, this switch in chemokine receptor expression was accentuated after acute LPS-induced lung inflammation. Collectively, these findings reveal a novel role for PAR1 and the chemokines, CCL2 and CCL7, during the early events of acute neutrophilic inflammation.
authors: 1 Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom.
authors: Paul F
authors: PF
authors: Mercer
authors: Andrew E
authors: AE
authors: Williams
authors: Christopher J
authors: CJ
authors: Scotton
authors: Ricardo J
authors: RJ
authors: José
authors: Michal
authors: M
authors: Sulikowski
authors: James D
authors: JD
authors: Moffatt
authors: Lynne A
authors: LA
authors: Murray
authors: Rachel C
authors: RC
authors: Chambers
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism*; D054410:Chemokine CCL7 / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D011014:Pneumonia / Q000378:metabolism* / Q000473:pathology*; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D044463:Receptor, PAR-1 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; C515451:Ccl7 protein, mouse; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D018925:Chemokines; D044463:Receptor, PAR-1; D019707:Receptors, Chemokine; D023063:Receptors, Interleukin-8B
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