Research
I have recently characterised a lung endothelial specific knock-out of HIFa isoforms to determine their role in pulmonary hypertension. Hypoxic pulmonary vasoconstriction initiates pulmonary vascular remodelling, which when prolonged leads to the development of pulmonary hypertension. The hypoxia-inducible transcription factors (HIFs), HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodelling, but the specific role of pulmonary endothelial HIF expression in this process has not been studied. I have shown that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension (PAH). The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic wild type (WT) mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Minimal pulmonary vascular remodelling was observed in lungs of mice with pulmonary endothelial deletion of HIF-2α following chronic hypoxia. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.
Publications
https://www.researchgate.net/profile/Andrew_Cowburn
Porter LM, Cowburn AS, Farahi N, Deighton J, Farrow SN, Fiddler CA, Juss JK, Condliffe AM, Chilvers ER. Hypoxia causes IL-8 secretion, Charcot Leyden crystal formation, and suppression of corticosteroid-induced apoptosis in human eosinophils. Clin Exp Allergy 2016 Dec 21 [Epub ahead of print]
Storisteanu DM, Pocock JM, Cowburn AS, Juss JK, Nadesalingam A, Nizet V, Chilvers ER. Evasion of Neutrophil Extracellular Traps by Respiratory Pathogens. Am J Respir Cell Mol Biol 2016 Nov 17. [Epub ahead of print]
Fiddler CA, Parfrey H, Cowburn AS, Luo D, Nash GB, Murphy G, Chilvers ER. The Aminopeptidase CD13 Induces Homotypic Aggregation in Neutrophils and Impairs Collagen Invasion. PLoSOne 2016 Jul 28;11(7)
*Cowburn AS, Crosby A, Macias D, Branco C, Colaco R, Southwood M, Toshner M, Crotty-Alexander LE, Morrell NW, Chilvers ER, Johnson RS. A HIF2a-arginase axis is essential for the development of pulmonary hypertension. Proc Natl Acad Sci U S A 2016 Aug 2;113(31):8801-6
Semba H, Takeda N, Isagawa T, Sugiura Y, Honda K, Wake M, Miyazawa H, Yamaguchi Y, Miura M, Jenkins DM, Choi H, Kim JW, Asagiri M, Cowburn AS, Abe H, Soma K, Koyama K, Katoh M, Sayama K, Goda N, Johnson RS, Manabe I, Nagai R, Komuro I. HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. Nat Commun 2016 May 18;7:11635
Ashmore T, Roberts LD, Morash AJ, Kotwica AO, Finnerty J, West JA, Murfitt SA, Fernandez BO, Branco C, Cowburn AS, Clarke K, Johnson RS, Feelisch M, Griffin JL, Murray AJ. Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism. BMC Biol 2015 Dec 22;13:110.
Cheng JP, Mendoza-Topaz C, Howard G, Chadwick J, Shvets E, Cowburn AS, Dunmore BJ, Crosby A, Morrell NW, Nichols BJ. Caveolae protect endothelial cells from membrane rupture during increased cardiac output. J Cell Biol 2015 Oct 12;211(1):53-61
Ashmore T, Fernandez BO, Branco-Price C, West JA, Cowburn AS, Heather LC, Griffin JL, Johnson RS, Feelisch M, Murray AJ. Dietary nitrate increases arginine availability and protects mitochondrial complex I and energetics in the hypoxic rat heart. J Physiol 2014 Nov 1;592(21):4715-31
*Cowburn AS, Alexander LE, Southwood M, Nizet V, Chilvers ER, Johnson RS. Epidermal Deletion of HIF-2α Stimulates Wound Closure. J Invest Dermatol 2014 Mar;134(3):801-8
*Cowburn AS, Takeda N, Boutin AT, Kim JW, Sterling JC, Nakasaki M, Southwood M, Goldrath AW, Jamora C, Nizet V, Chilvers ER, Johnson RS. HIF isoforms in the skin differentially regulate systemic arterial pressure. Proc Natl Acad Sci U S A 2013 Oct 22;110(43):17570-5
Crotty Alexander LE, Akong-Moore K, Feldstein S, Johansson P, Nguyen A, McEachern EK, Nicatia S, Cowburn AS, Olson J, Cho JY, Isaacs H Jr, Johnson RS, Broide DH, Nizet V. Myeloid cell HIF-1α regulates asthma airway resistance and eosinophil function. J Mol Med 2013 May;91(5):637-44
Juss JK, Hayhoe RP, Owen CE, Bruce I, Walmsley SR, Cowburn AS, Kulkarni S, Boyle KB, Stephens L, Hawkins PT, Chilvers ER, Condliffe AM. Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. PLoSOne 2012;7(9):e45933
McGovern NN, Cowburn AS, Porter L, Walmsley SR, Summers C, Thompson AA, Anwar S, Willcocks LC, Whyte MK, Condliffe AM, Chilvers ER. Hypoxia selectively inhibits respiratory burst activity and killing of Staphylococcus aureus in human neutrophils. J Immunol 2011 Jan 1;186(1):453-63
*Cowburn AS, Summers C, Dunmore BJ, Farahi N, Hayhoe RP, Print CG, Cook SJ,Chilvers ER. Granulocyte/macrophage colony-stimulating factor causes a paradoxicalincrease in the BH3-only pro-apoptotic protein Bim in human neutrophils. Am J Respir Cell Mol Biol 2011 Jun;44(6):879-87
Cowburn AS, Condliffe AM, Farahi N, Summers C, Chilvers ER. Advances in neutrophil biology: clinical implications. Chest 2008 Sep;134(3):606-12
Farahi N, Cowburn AS, Upton PD, Deighton J, Sobolewski A, Gherardi E, Morrell NW, Chilvers ER. Eotaxin-1/CC chemokine ligand 11: a novel eosinophil survival factor secreted by human pulmonary artery endothelial cells. J Immunol 2007 Jul15;179(2):1264-73
*Walmsley SR, Cowburn AS, Clatworthy MR, Morrell NW, Roper EC, Singleton V, Maxwell P, Whyte MK, Chilvers ER. Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis. Blood 2006 Nov 1;108(9):3176-8
*Cowburn AS, Sobolewski A, Reed BJ, Deighton J, Murray J, Cadwallader KA, Bradley JR, Chilvers ER. Aminopeptidase N (CD13) regulates tumor necrosis factor-alphainduced apoptosis in human neutrophils. J Biol Chem 2006 May 5;281(18):12458-67
Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, Chilvers ER. Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 2005 Jan 3;201(1):105-15
*Cowburn AS, White JF, Deighton J, Walmsley SR, Chilvers ER. z-VAD-fmk augmentation of TNF alpha-stimulated neutrophil apoptosis is compound specific and does not involve the generation of reactive oxygen species. Blood 2005 Apr 1;105(7):2970-2
Cowburn AS, Deighton J, Walmsley SR, Chilvers ER. The survival effect of TNF-alpha in human neutrophils is mediated via NF-kappa B-dependent IL-8 release. Eur J Immunol 2004 Jun;34(6):1733-43
Walmsley SR, Cowburn AS, Sobolewski A, Murray J, Farahi N, Sabroe I, Chilvers ER. Characterization of the survival effect of tumour necrosis factor-alpha in human neutrophils. Biochem Soc Trans 2004 Jun;32(Pt3):456-60
Mecklenburgh KI, Walmsley SR, Cowburn AS, Wiesener M, Reed BJ, Upton PD, Deighton J, Greening AP, Chilvers ER. Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis. Blood 2002 Oct 15;100(8):3008-16
*Cowburn AS, Cadwallader KA, Reed BJ, Farahi N, Chilvers ER. Role of PI3-kinasedependent Bad phosphorylation and altered transcription in cytokine-mediated neutrophil survival. Blood 2002 Oct 1;100(7):2607-16
Condliffe AM, Cadwallader KA, Walker TR, Rintoul RC, Cowburn AS, Chilvers ER. Phosphoinositide 3-kinase: a critical signalling event in pulmonary cells. Respir Res 2000;1(1):24-9
*Cowburn AS, Holgate ST, Sampson AP. IL-5 increases expression of 5-lipoxygenaseactivating protein and translocates 5-lipoxygenase to the nucleus in human blood eosinophils. J Immunol 1999 Jul 1;163(1):456-65
*Cowburn AS, Sladek K, Soja J, Adamek L, Nizankowska E, Szczeklik A, Lam BK, Penrose JF, Austen FK, Holgate ST, Sampson AP. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 1998 Feb 15;101(4):834-46
