Mercer, PF;
Williams, AE;
Scotton, CJ;
José, RJ;
Sulikowski, M;
Moffatt, JD;
Murray, LA;
(2014)
Proteinase-Activated Receptor-1, CCL2 and CCL7 Regulate Acute Neutrophilic Lung Inflammation.
American Journal of Respiratory Cell and Molecular Biology
, 50
(1)
pp. 144-157.
10.1165/rcmb.2013-0142OC.
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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 pro-inflammatory cytokines TNF and IL-6 or the classic neutrophil chemoattractants CXCL1 and CXCL2. Antibody neutralisation 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 CCL2 predominantly localised to alveolar macrophages and pulmonary epithelial cells, while CCL7 was restricted to the pulmonary epithelium. In keeping with these observations, the intranasal administration of rCCL2 and rCCL7 led to the accumulation of neutrophils within the lung airspaces of naïve mice in the absence of any underlying inflammation. Flow cytometry analysis further demonstrated an increase in Ly6Ghi neutrophils expressing the chemokine receptors CCR1 and CCR2 isolated from mouse lungs compared to circulating neutrophils. Conversely, the expression of CXCR2 decreased on neutrophils isolated from the lung compared to circulating neutrophils. Furthermore, this switch in chemokine receptor expression was accentuated following 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.
| Type: | Article |
|---|---|
| Title: | Proteinase-Activated Receptor-1, CCL2 and CCL7 Regulate Acute Neutrophilic Lung Inflammation |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1165/rcmb.2013-0142OC |
| Publisher version: | http://dx.doi.org/10.1165/rcmb.2013-0142OC |
| Language: | English |
| Additional information: | Originally Published in: Paul F. Mercer, Andrew E. Williams, Christopher J. Scotton, Ricardo J. José, Michal Sulikowski, James D. Moffatt, Lynne A. Murray, and Rachel C. Chambers. Proteinase-Activated Receptor-1, CCL2, and CCL7 Regulate Acute Neutrophilic Lung Inflammation. American Journal of Respiratory Cell and Molecular Biology 2014;50(1):144-157. DOI: 10.1165/rcmb.2013-0142OC. Copyright © 2015 by the American Thoracic Society. The final publication is available at http://dx.doi.org/10.1165/rcmb.2013-0142OC. |
| Keywords: | inflammation, lung, neutrophil, chemokine, proteinase-activated receptor-1 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Education UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1404540 |
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