Increased hypoxia-inducible factor 1α expression in lung cells of horses with recurrent airway obstruction.
Abstract: Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological processes responsible for the development and the persistence of airway inflammation are still largely unknown. Hypoxia-inducible factor (Hif) is mainly known as a major regulator of energy homeostasis and cellular adaptation to hypoxia. More recently however, Hif also emerged as an essential regulator of innate immune responses. Here, we aimed at investigating the potential involvement of Hif1-α in myeloid cells in horse with recurrent airway obstruction. Results: In vitro, we observed that Hif is expressed in equine myeloid cells after hay dust stimulation and regulates genes such as tumor necrosis factor alpha (TNF-α), interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A). We further showed in vivo that airway challenge with hay dust upregulated Hif1-α mRNA expression in myeloid cells from the bronchoalveolar lavage fluid (BALF) of healthy and RAO-affected horses, with a more pronounced effect in cells from RAO-affected horses. Finally, Hif1-α mRNA expression in BALF cells from challenged horses correlated positively with lung dysfunction. Conclusions: Taken together, our results suggest an important role for Hif1-α in myeloid cells during hay dust-induced inflammation in horses with RAO. We therefore propose that future research aiming at functional inactivation of Hif1 in lung myeloid cells could open new therapeutic perspectives for RAO.
Publication Date: 2012-05-23 PubMed ID: 22621400PubMed Central: PMC3536633DOI: 10.1186/1746-6148-8-64Google Scholar: Lookup
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- Journal Article
Summary
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The study reveals a possible link between increased Hypoxia-inducible factor 1α (Hif1-α) expression in lung cells and recurrent airway obstruction (RAO) in horses. The research showed that Hif has an important role in the inflammation caused by hay dust in horses suffering from RAO.
Research Objectives and Background
- The study aimed to investigate the role of Hypoxia-inducible factor 1α (Hif1-α) in equine myeloid cells during Recurrent Airway Obstruction (RAO), an inflammatory condition in horses that results from exposure to organic dusts in hay.
- Previously, Hif had been recognized as a vital regulator of energy homeostasis and cellular adaptation to hypoxia. However, recent studies show that Hif also regulates innate immune responses, indicating a possible role in the development and persistence of airway inflammation in RAO.
Methodology and Results
- The study involved in vitro observation where researchers noted that Hif expression occurs in equine myeloid cells when stimulated by hay dust. This Hif expression also regulated genes like tumor necrosis factor alpha (TNF-α), interleukin-8 (IL-8), and vascular endothelial growth factor A (VEGF-A).
- Through in vivo studies, the study found that a challenge with hay dust upregulated Hif1-α mRNA expression in myeloid cells from bronchoalveolar lavage fluid (BALF). The effect was more significant in cells from RAO-affected horses.
- The study observed a positive correlation between Hif1-α mRNA expression in BALF cells from dust-challenged horses and lung dysfunction, hinting at Hif1-α’s crucial role in the hay dust-induced inflammation in RAO horses.
Conclusions and Future Directions
- The study concluded that the Hif1-α in myeloid cells has a significant role in hay dust-induced inflammation seen in horses with RAO.
- As a result of these findings, the study proposes further research to explore the option of functionally inactivating Hif1 in lung myeloid cells, which could open new therapeutic avenues for treating RAO.
Cite This Article
APA
Toussaint M, Fievez L, Desmet CJ, Pirottin D, Farnir F, Bureau F, Lekeux P.
(2012).
Increased hypoxia-inducible factor 1α expression in lung cells of horses with recurrent airway obstruction.
BMC Vet Res, 8, 64.
https://doi.org/10.1186/1746-6148-8-64 Publication
Researcher Affiliations
- Laboratory of Cellular and Molecular Physiology, GIGA-Research and Faculty of Veterinary Medicine, University of Liège, B34-Avenue de l'Hôpital, 1, 4000, Liège, Belgium. M.Toussaint@ulg.ac.be
MeSH Terms
- Animals
- Antitussive Agents / pharmacology
- Cells, Cultured
- Dust
- Gene Expression Regulation / physiology
- Horse Diseases / metabolism
- Horses
- Hypoxia-Inducible Factor 1, alpha Subunit / genetics
- Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
- Inflammation / metabolism
- Inflammation / veterinary
- Interleukin-8 / genetics
- Interleukin-8 / metabolism
- Lung / cytology
- Lung / metabolism
- Lung Diseases, Obstructive / metabolism
- Lung Diseases, Obstructive / veterinary
- Monocytes / drug effects
- Monocytes / metabolism
- Noscapine / pharmacology
- RNA, Messenger / genetics
- RNA, Messenger / metabolism
- Tumor Necrosis Factor-alpha / genetics
- Tumor Necrosis Factor-alpha / metabolism
- Vascular Endothelial Growth Factor A / genetics
- Vascular Endothelial Growth Factor A / metabolism
References
This article includes 52 references
- Derksen FJ, Scott JS, Miller DC, Slocombe RF, Robinson NE. Bronchoalveolar lavage in ponies with recurrent airway obstruction (heaves).. Am Rev Respir Dis 1985 Nov;132(5):1066-70.
- LOWELL FC. OBSERVATIONS ON HEAVES. AN ASTHMA-LIKE SYNDROME IN THE HORSE.. J Allergy 1964 Jul-Aug;35:322-30.
- Robinson NE. International Workshop on Equine Chronic Airway Disease. Michigan State University 16-18 June 2000.. Equine Vet J 2001 Jan;33(1):5-19.
- Mair TS. Changing concepts of COPD.. Equine Vet J 1995 Nov;27(6):402-3.
- Pirie RS, Dixon PM, McGorum BC. Endotoxin contamination contributes to the pulmonary inflammatory and functional response to Aspergillus fumigatus extract inhalation in heaves horses.. Clin Exp Allergy 2003 Sep;33(9):1289-96.
- Wagner B. IgE in horses: occurrence in health and disease.. Vet Immunol Immunopathol 2009 Nov 15;132(1):21-30.
- Lavoie JP, Maghni K, Desnoyers M, Taha R, Martin JG, Hamid QA. Neutrophilic airway inflammation in horses with heaves is characterized by a Th2-type cytokine profile.. Am J Respir Crit Care Med 2001 Oct 15;164(8 Pt 1):1410-3.
- Ainsworth DM, Grünig G, Matychak MB, Young J, Wagner B, Erb HN, Antczak DF. Recurrent airway obstruction (RAO) in horses is characterized by IFN-gamma and IL-8 production in bronchoalveolar lavage cells.. Vet Immunol Immunopathol 2003 Nov 15;96(1-2):83-91.
- Cordeau ME, Joubert P, Dewachi O, Hamid Q, Lavoie JP. IL-4, IL-5 and IFN-gamma mRNA expression in pulmonary lymphocytes in equine heaves.. Vet Immunol Immunopathol 2004 Jan;97(1-2):87-96.
- Horohov DW, Beadle RE, Mouch S, Pourciau SS. Temporal regulation of cytokine mRNA expression in equine recurrent airway obstruction.. Vet Immunol Immunopathol 2005 Oct 18;108(1-2):237-45.
- Kleiber C, McGorum BC, Horohov DW, Pirie RS, Zurbriggen A, Straub R. Cytokine profiles of peripheral blood and airway CD4 and CD8 T lymphocytes in horses with recurrent airway obstruction.. Vet Immunol Immunopathol 2005 Mar 10;104(1-2):91-7.
- Karhausen J, Haase VH, Colgan SP. Inflammatory hypoxia: role of hypoxia-inducible factor.. Cell Cycle 2005 Feb;4(2):256-8.
- Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.. Science 2001 Apr 20;292(5516):468-72.
- McNeill LA, Hewitson KS, Claridge TD, Seibel JF, Horsfall LE, Schofield CJ. Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the beta-carbon of asparagine-803.. Biochem J 2002 Nov 1;367(Pt 3):571-5.
- Saadi S, Wrenshall LE, Platt JL. Regional manifestations and control of the immune system.. FASEB J 2002 Jun;16(8):849-56.
- Sitkovsky M, Lukashev D. Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors.. Nat Rev Immunol 2005 Sep;5(9):712-21.
- Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia.. J Appl Physiol (1985) 2000 Apr;88(4):1474-80.
- Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha.. Nature 2008 Jun 5;453(7196):807-11.
- Jantsch J, Wiese M, Schödel J, Castiglione K, Gläsner J, Kolbe S, Mole D, Schleicher U, Eckardt KU, Hensel M, Lang R, Bogdan C, Schnare M, Willam C. Toll-like receptor activation and hypoxia use distinct signaling pathways to stabilize hypoxia-inducible factor 1α (HIF1A) and result in differential HIF1A-dependent gene expression.. J Leukoc Biol 2011 Sep;90(3):551-62.
- Mahabeleshwar GH, Kawanami D, Sharma N, Takami Y, Zhou G, Shi H, Nayak L, Jeyaraj D, Grealy R, White M, McManus R, Ryan T, Leahy P, Lin Z, Haldar SM, Atkins GB, Wong HR, Lingrel JB, Jain MK. The myeloid transcription factor KLF2 regulates the host response to polymicrobial infection and endotoxic shock.. Immunity 2011 May 27;34(5):715-28.
- Hellwig-Bürgel T, Rutkowski K, Metzen E, Fandrey J, Jelkmann W. Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1.. Blood 1999 Sep 1;94(5):1561-7.
- Blouin CC, Pagé EL, Soucy GM, Richard DE. Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1alpha.. Blood 2004 Feb 1;103(3):1124-30.
- Görlach A, Bonello S. The cross-talk between NF-kappaB and HIF-1: further evidence for a significant liaison.. Biochem J 2008 Jun 15;412(3):e17-9.
- Huerta-Yepez S, Baay-Guzman GJ, Garcia-Zepeda R, Hernandez-Pando R, Vega MI, Gonzalez-Bonilla C, Bonavida B. 2-Methoxyestradiol (2-ME) reduces the airway inflammation and remodeling in an experimental mouse model.. Clin Immunol 2008 Nov;129(2):313-24.
- Huerta-Yepez S, Baay-Guzman GJ, Bebenek IG, Hernandez-Pando R, Vega MI, Chi L, Riedl M, Diaz-Sanchez D, Kleerup E, Tashkin DP, Gonzalez FJ, Bonavida B, Zeidler M, Hankinson O. Hypoxia inducible factor promotes murine allergic airway inflammation and is increased in asthma and rhinitis.. Allergy 2011 Jul;66(7):909-18.
- Frede S, Stockmann C, Freitag P, Fandrey J. Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB.. Biochem J 2006 Jun 15;396(3):517-27.
- Ashitani J, Kyoraku Y, Yanagi S, Matsumoto N, Nakazato M. Elevated levels of beta-D-glucan in bronchoalveolar lavage fluid in patients with farmer's lung in Miyazaki, Japan.. Respiration 2008;75(2):182-8.
- McCann F, Carmona E, Puri V, Pagano RE, Limper AH. Macrophage internalization of fungal beta-glucans is not necessary for initiation of related inflammatory responses.. Infect Immun 2005 Oct;73(10):6340-9.
- Mi Z, Rapisarda A, Taylor L, Brooks A, Creighton-Gutteridge M, Melillo G, Varesio L. Synergystic induction of HIF-1alpha transcriptional activity by hypoxia and lipopolysaccharide in macrophages.. Cell Cycle 2008 Jan 15;7(2):232-41.
- Sandersen C, Bureau F, Turlej R, Fiévez L, Dogné S, Kirschvink N, Lekeux P. p65 Homodimer activity in distal airway cells determines lung dysfunction in equine heaves.. Vet Immunol Immunopathol 2001 Aug 10;80(3-4):315-26.
- Fang HY, Hughes R, Murdoch C, Coffelt SB, Biswas SK, Harris AL, Johnson RS, Imityaz HZ, Simon MC, Fredlund E, Greten FR, Rius J, Lewis CE. Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia.. Blood 2009 Jul 23;114(4):844-59.
- Liu FQ, Liu Y, Lui VC, Lamb JR, Tam PK, Chen Y. Hypoxia modulates lipopolysaccharide induced TNF-alpha expression in murine macrophages.. Exp Cell Res 2008 Apr 1;314(6):1327-36.
- An HJ, Kim IT, Park HJ, Kim HM, Choi JH, Lee KT. Tormentic acid, a triterpenoid saponin, isolated from Rosa rugosa, inhibited LPS-induced iNOS, COX-2, and TNF-α expression through inactivation of the nuclear factor-κb pathway in RAW 264.7 macrophages.. Int Immunopharmacol 2011 Apr;11(4):504-10.
- Laan TT, Bull S, Pirie R, Fink-Gremmels J. The role of alveolar macrophages in the pathogenesis of recurrent airway obstruction in horses.. J Vet Intern Med 2006 Jan-Feb;20(1):167-74.
- Bureau F, Delhalle S, Bonizzi G, Fiévez L, Dogné S, Kirschvink N, Vanderplasschen A, Merville MP, Bours V, Lekeux P. Mechanisms of persistent NF-kappa B activity in the bronchi of an animal model of asthma.. J Immunol 2000 Nov 15;165(10):5822-30.
- Hirani N, Antonicelli F, Strieter RM, Wiesener MS, Ratcliffe PJ, Haslett C, Donnelly SC. The regulation of interleukin-8 by hypoxia in human macrophages--a potential role in the pathogenesis of the acute respiratory distress syndrome (ARDS).. Mol Med 2001 Oct;7(10):685-97.
- Franchini M, Gill U, von Fellenberg R, Bracher VD. Interleukin-8 concentration and neutrophil chemotactic activity in bronchoalveolar lavage fluid of horses with chronic obstructive pulmonary disease following exposure to hay.. Am J Vet Res 2000 Nov;61(11):1369-74.
- Hatoum OA, Miura H, Binion DG. The vascular contribution in the pathogenesis of inflammatory bowel disease.. Am J Physiol Heart Circ Physiol 2003 Nov;285(5):H1791-6.
- Gomułka K, Liebhart J. [Vascular endothelial growth factor - structure, function and role in airways inflammation and the clinical course of asthma].. Pneumonol Alergol Pol 2009;77(6):549-53.
- Lee SY, Kwon S, Kim KH, Moon HS, Song JS, Park SH, Kim YK. Expression of vascular endothelial growth factor and hypoxia-inducible factor in the airway of asthmatic patients.. Ann Allergy Asthma Immunol 2006 Dec;97(6):794-9.
- Gordon S, Taylor PR. Monocyte and macrophage heterogeneity.. Nat Rev Immunol 2005 Dec;5(12):953-64.
- Ueno M, Maeno T, Nomura M, Aoyagi-Ikeda K, Matsui H, Hara K, Tanaka T, Iso T, Suga T, Kurabayashi M. Hypoxia-inducible factor-1α mediates TGF-β-induced PAI-1 production in alveolar macrophages in pulmonary fibrosis.. Am J Physiol Lung Cell Mol Physiol 2011 May;300(5):L740-52.
- Frede S, Stockmann C, Winning S, Freitag P, Fandrey J. Hypoxia-inducible factor (HIF) 1alpha accumulation and HIF target gene expression are impaired after induction of endotoxin tolerance.. J Immunol 2009 May 15;182(10):6470-6.
- Schuster DP, Brody SL, Zhou Z, Bernstein M, Arch R, Link D, Mueckler M. Regulation of lipopolysaccharide-induced increases in neutrophil glucose uptake.. Am J Physiol Lung Cell Mol Physiol 2007 Apr;292(4):L845-51.
- Britten KM, Howarth PH, Roche WR. Immunohistochemistry on resin sections: a comparison of resin embedding techniques for small mucosal biopsies.. Biotech Histochem 1993 Sep;68(5):271-80.
- Robinson NE, Olszewski MA, Boehler D, Berney C, Hakala J, Matson C, Derksen FJ. Relationship between clinical signs and lung function in horses with recurrent airway obstruction (heaves) during a bronchodilator trial.. Equine Vet J 2000 Sep;32(5):393-400.
- Van Erck E, Votion D, Art T, Lekeux P. Qualitative and quantitative evaluation of equine respiratory mechanics by impulse oscillometry.. Equine Vet J 2006 Jan;38(1):52-8.
- van Erck E, Votion D, Art T, Lekeux P. Measurement of respiratory function by impulse oscillometry in horses.. Equine Vet J 2004 Jan;36(1):21-8.
- Pirie RS, McLachlan G, McGorum BC. Evaluation of nebulised hay dust suspensions (HDS) for the diagnosis and investigation of heaves. 1: Preparation and composition of HDS.. Equine Vet J 2002 Jul;34(4):332-6.
- Newcomb EW, Lukyanov Y, Schnee T, Ali MA, Lan L, Zagzag D. Noscapine inhibits hypoxia-mediated HIF-1alpha expression andangiogenesis in vitro: a novel function for an old drug.. Int J Oncol 2006 May;28(5):1121-30.
- Newcomb EW, Lukyanov Y, Smirnova I, Schnee T, Zagzag D. Noscapine induces apoptosis in human glioma cells by an apoptosis-inducing factor-dependent pathway.. Anticancer Drugs 2008 Jul;19(6):553-63.
- Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes.. Genome Biol 2002 Jun 18;3(7):RESEARCH0034.
Citations
This article has been cited 5 times.- Padoan E, Ferraresso S, Pegolo S, Barnini C, Castagnaro M, Bargelloni L. Gene Expression Profiles of the Immuno-Transcriptome in Equine Asthma.. Animals (Basel) 2022 Dec 20;13(1).
- Niedzwiedz A, Borowicz H, Januszewska L, Markiewicz-Gorka I, Jaworski Z. Serum 8-hydroxy-2-deoxyguanosine as a marker of DNA oxidative damage in horses with recurrent airway obstruction.. Acta Vet Scand 2016 Jun 7;58(1):38.
- Xu W, Guo G, Li J, Ding Z, Sheng J, Li J, Tan W. Activation of Bcl-2-Caspase-9 Apoptosis Pathway in the Testis of Asthmatic Mice.. PLoS One 2016;11(3):e0149353.
- Pacholewska A, Jagannathan V, Drögemüller M, Klukowska-Rötzler J, Lanz S, Hamza E, Dermitzakis ET, Marti E, Leeb T, Gerber V. Impaired Cell Cycle Regulation in a Natural Equine Model of Asthma.. PLoS One 2015;10(8):e0136103.
- Kim J, Choi IY, Dong Y, Wang WT, Brooks WM, Weiner CP, Lee P. Chronic fetal hypoxia affects axonal maturation in guinea pigs during development: A longitudinal diffusion tensor imaging and T2 mapping study.. J Magn Reson Imaging 2015 Sep;42(3):658-65.
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