BACKGROUND: New therapies are necessary to address inadequate asthma control in many patients. This study sets out to investigate whether hypoxia-inducible factor (HIF) is essential for development of allergic airway inflammation (AAI) and therefore a potential novel target for asthma treatment. METHODS: Mice conditionally knocked out for HIF-1β were examined for their ability to mount an allergic inflammatory response in the lung after intratracheal exposure to ovalbumin. The effects of treating wild-type mice with either ethyl-3,4-dihydroxybenzoate (EDHB) or 2-methoxyestradiol (2ME), which upregulate and downregulate HIF, respectively, were determined. HIF-1α levels were also measured in endobronchial biopsies and bronchial fluid of patients with asthma and nasal fluid of patients with rhinitis after challenge. RESULTS: Deletion of HIF-1β resulted in diminished AAI and diminished production of ovalbumin-specific IgE and IgG(1) . EDHB enhanced the inflammatory response, which was muted upon simultaneous inhibition of vascular endothelial growth factor (VEGF). EDHB and 2ME antagonized each other with regard to their effects on airway inflammation and mucus production. The levels of HIF-1α and VEGF increased in lung tissue and bronchial fluid of patients with asthma and in the nasal fluid of patients with rhinitis after challenge. CONCLUSIONS: Our results support the notion that HIF is directly involved in the development of AAI. Most importantly, we demonstrate for the first time that HIF-1α is increased after challenge in patients with asthma and rhinitis. Therefore, we propose that HIF may be a potential therapeutic target for asthma and possibly for other inflammatory diseases.
BACKGROUND: New therapies are necessary to address inadequate asthma control in many patients. This study sets out to investigate whether hypoxia-inducible factor (HIF) is essential for development of allergic airway inflammation (AAI) and therefore a potential novel target for asthma treatment. METHODS:Mice conditionally knocked out for HIF-1β were examined for their ability to mount an allergic inflammatory response in the lung after intratracheal exposure to ovalbumin. The effects of treating wild-type mice with either ethyl-3,4-dihydroxybenzoate (EDHB) or 2-methoxyestradiol (2ME), which upregulate and downregulate HIF, respectively, were determined. HIF-1α levels were also measured in endobronchial biopsies and bronchial fluid of patients with asthma and nasal fluid of patients with rhinitis after challenge. RESULTS: Deletion of HIF-1β resulted in diminished AAI and diminished production of ovalbumin-specific IgE and IgG(1) . EDHB enhanced the inflammatory response, which was muted upon simultaneous inhibition of vascular endothelial growth factor (VEGF). EDHB and 2ME antagonized each other with regard to their effects on airway inflammation and mucus production. The levels of HIF-1α and VEGF increased in lung tissue and bronchial fluid of patients with asthma and in the nasal fluid of patients with rhinitis after challenge. CONCLUSIONS: Our results support the notion that HIF is directly involved in the development of AAI. Most importantly, we demonstrate for the first time that HIF-1α is increased after challenge in patients with asthma and rhinitis. Therefore, we propose that HIF may be a potential therapeutic target for asthma and possibly for other inflammatory diseases.
Authors: Eric D Bateman; Homer A Boushey; Jean Bousquet; William W Busse; Tim J H Clark; Romain A Pauwels; Søren E Pedersen Journal: Am J Respir Crit Care Med Date: 2004-07-15 Impact factor: 21.405
Authors: Nicola J Mabjeesh; Daniel Escuin; Theresa M LaVallee; Victor S Pribluda; Glenn M Swartz; Michelle S Johnson; Margaret T Willard; Hua Zhong; Jonathan W Simons; Paraskevi Giannakakou Journal: Cancer Cell Date: 2003-04 Impact factor: 31.743
Authors: Krista K Greenwood; Steven P Proper; Yogesh Saini; Lori A Bramble; Daven N Jackson-Humbles; James G Wagner; Jack R Harkema; John J LaPres Journal: Am J Physiol Lung Cell Mol Physiol Date: 2011-12-16 Impact factor: 5.464
Authors: Nels Olson; Milena Hristova; Nicholas H Heintz; Karen M Lounsbury; Albert van der Vliet Journal: Am J Physiol Lung Cell Mol Physiol Date: 2011-09-16 Impact factor: 5.464
Authors: Qin Wei; Youbao Sha; Abhisek Bhattacharya; Elmoataz Abdel Fattah; Diana Bonilla; Soma S S K Jyothula; Lavannya Pandit; Gurjit K Khurana Hershey; N Tony Eissa Journal: Am J Respir Crit Care Med Date: 2014-01-01 Impact factor: 21.405
Authors: Laura E Crotty Alexander; Kathryn Akong-Moore; Stephanie Feldstein; Per Johansson; Anh Nguyen; Elisa K McEachern; Shari Nicatia; Andrew S Cowburn; Joshua Olson; Jae Youn Cho; Hart Isaacs; Randall S Johnson; David H Broide; Victor Nizet Journal: J Mol Med (Berl) Date: 2012-12-19 Impact factor: 4.599
Authors: Kwang Je Baek; Jae Youn Cho; Peter Rosenthal; Laura E Crotty Alexander; Victor Nizet; David H Broide Journal: Clin Immunol Date: 2013-02-21 Impact factor: 3.969
Authors: Xiao Na Ge; Yana Greenberg; M Reza Hosseinkhani; Eric K Long; Nooshin S Bahaie; Amrita Rao; Sung Gil Ha; Savita P Rao; David A Bernlohr; P Sriramarao Journal: Exp Lung Res Date: 2013-10-08 Impact factor: 2.459