Projects per year
Abstract
Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (Ri) from 19 to 7 h and improved organ dysfunction with enhanced alveolar-capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (Ri; 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation.
Original language | English |
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Pages (from-to) | 857-868 |
Number of pages | 12 |
Journal | Mucosal Immunology |
Volume | 7 |
Issue number | 4 |
Early online date | 27 Nov 2013 |
DOIs | |
Publication status | Published - Jul 2014 |
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Dive into the research topics of 'Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung'. Together they form a unique fingerprint.Projects
- 3 Finished
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The role of cyclin-dependent kinase-9 inhibition in promoting the resolution of chronic inflammation
Rossi, A. (Principal Investigator) & Haslett, C. (Co-investigator)
1/05/13 → 30/10/19
Project: Research
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Edinburgh Clinical Academic Track (ECAT) training Programme - Dr Christopher Lucas
Rossi, A. (Principal Investigator)
1/08/10 → 31/07/13
Project: Research
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Induction of neutrophil apoptosis and treatment of severe lung inflammation
Rossi, A. (Principal Investigator)
1/09/07 → 29/02/12
Project: Research
Profiles
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Rodger Duffin
- Deanery of Clinical Sciences - Personal Chair of Thoracic Toxicology
- Centre for Inflammation Research
Person: Academic: Research Active
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Christopher Lucas
- Deanery of Clinical Sciences - MRC Clinician Scientist
- Centre for Inflammation Research
Person: Academic: Research Active