Exposure to the Interior Environment of Water-Damaged Buildings Can Activate HIF 1A, Induce Proliferative Physiology and Impair Mitochondrial Metabolism

Main Article Content

Shoemaker R Heyman A Lark D

Abstract

Hypoxia-inducible factor 1A (HIF 1A) is an oxygen-sensing nuclear transcription factor that regulates oxygen homeostasis in many illnesses ranging from, but not limited to, cancer, heart failure, premature infants to viral infections. We report here the measurement of HIF 1A using transcriptomics as a biomarker in Chronic Inflammatory Response Syndrome (CIRS), a systemic inflammatory and metabolic illness characterized by a multisystem, multi-symptom illness acquired following exposure to the interior environment of water-damaged buildings (WDB).


Pulmonary artery hypertension (PAH) is a well-established disease and is also associated with CIRS, but treatment is problematic, depending on its physiologic basis.


Both CIRS and PAH share a common pathogenesis of proliferative physiology. In the case of CIRS, genomic overexpression of the HIF 1A pathway represents a particularly concerning finding in our study population. Its re-regulation offers a salutary outcome, with the benefit of reducing the phenotypic expression represented by resolving PAH. By first reviewing the diverse pathophysiology of PAH, we present data that provide a basis for the demonstrated efficacy of our treatment protocol, which was used sequentially in CIRS patients to reduce HIF 1A by resolving aberrant mitochondrial transcriptomics associated with proliferative physiology and molecular hypometabolism. These data suggest a basis for a novel approach to treatment of PAH.


We demonstrate reduction of HIF 1A by a CIRS-treatment protocol with VIP therapy in the context of proper biotoxin treatment. Current literature shows that reduction of HIF 1A is crucial in PAH to avoid the significant morbidity and mortality associated with this condition.

Article Details

How to Cite
R, Shoemaker; A, Heyman; D, Lark. Exposure to the Interior Environment of Water-Damaged Buildings Can Activate HIF 1A, Induce Proliferative Physiology and Impair Mitochondrial Metabolism. Medical Research Archives, [S.l.], v. 12, n. 3, mar. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/5182>. Date accessed: 13 apr. 2024. doi: https://doi.org/10.18103/mra.v12i3.5182.
Section
Research Articles

References

1. Wang N, Hua J, An J, et al. Updated perspective of EPAS1 and the role in pulmonary hypertension. Frontiers 2023; Doi: 10.3389.
2. Ryan J, Dasgupta A, Huston J, et al. Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med 2015; 93: 229-242.
3. Ferreira A, Serejo J, Durans R, et.al. Dose-related effects of resveratrol in different models of pulmonary arterial hypertension: A systematic review. Curr Cardio Rev 2020; 16: 231-240.
4. Zeidan E, Akbar Hossain M, El-Daly M, et al. Mitochondrial regulation of the hypoxia-induced factor in the development of pulmonary hypertension. J. Clin Med 2022; 11: 5219.
5. Shoemaker R, House D, Ryan J. Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings. Health 2013; 5(3): 396-401.
6. Liu X, Zhang L, Zhang W. Metabolic reprogramming: A novel metabolic model for pulmonary hypertension. Review 2022; 10.3389/fcvm
7. Bryant A, Carrick R, McConaha M, et al. Endothelial HIF regulates pulmonary fibrosis-associated pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2016; 310: L249-L262.
8. Stenmark K, Tuder R, Kasmi K. Metabolic reprogramming and inflammation act in concert to control vascular remodeling in hypoxic pulmonary hypertension. J Appl Physiol 1985; 119: 1164-1
9. Cuttica MJ, Kalhan R, Shlobin OA, Ahmad S, Gladwin M, Machado RF, Barnett SD, Nathan SD. Categorization and impact of pulmonary hypertension in patients with advanced COPD. Respir Med 2010; 104: 1877-1882.
10. Fijalkowska I, Xu W, Comhair SA, Janocha AJ, Mavrakis LA, Krishnamachary B, Zhen L, Mao T, Richter A, Erzurum SC, Tuder RM. Hypoxia inducible-factor alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol 2010; 176: 1130-1138.
11. Paulin R, Michelakis ED. The metabolic theory of pulmonary arterial hypertension. Circ Res 2014; 115: 148-164.
12. Tuder RM, Archer SL, Dorfmuller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D4-D12.
13. Zhao L, Ashek A, Wang L, fang W, Dabral S, Dubois O, Cupitt J, Pullamsetti SS, Cotroneo E, Jones H, Tomasi G, Nguyen QD, Aboagye EO, El-Bahrawy MA, Barnes G, Howard LS, Gibbs JS. Gsell W, He JG, Gsell W. He JG, Wilkins MR. Heterogeneity in the lung (18) FDG uptake in pulmonary hypertension: the potential of dynamic (18) FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments 2013; 128: 1214-1224.
14. Jaitovich A, Jourd'heuil D. A brief overview of nitric oxide and reactive oxygen species signaling in hypoxia-induced pulmonary hypertension. Adv Exp Med Biol 2017; 967: 71-81
15. Labrousse-Aria D, Castillo-Gonzalez C, Rogers N, et al. HIF-2a-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction. Cardiovascular Research 2016; 109: 115-130
16. Lei W, Shui X, Li G, et al. Expression and analysis of the HIF-1 pathway in humans with pulmonary arterial hypertension lungs. Mol Med Rep 2016; 14: 4383-4390.
17. Han X, Zhang W, Wang Q et al. HIF 1A promotes the proliferation and migration of pulmonary arterial smooth muscle cells via activation of Cx43 Cell Moll Med. 2022; 25: 10663-10673.
18. Marshall J, Bazan L, Zhang Y, Fares W, Lee J. Mitochondrial dysfunction and pulmonary hypertension: Cause, effect or both? Am J Physio Cell Molec Phys, 2018; 314: L782?
19. McElroy G, Chandel N. Mitochondria control acute and chronic responses to hypoxia. Exp Cell Res.2017; 356:217.
20. Shoemaker, R. Metabolism, molecular hypometabolism and inflammation: Complications of proliferative physiology include metabolic acidosis, pulmonary hypertension, T reg cell deficiency, insulin resistance and neuronal injury. Trends Diabetes Metab 2021; Doi: 10.15761/TDM.1000118
21. Kracun D, Klop M, Knirsch A, et al. NADPH oxidase and HIF1 promote cardiac dysfunction and pulmonary hypertension in response to glucocorticoid excess. Redox Biology 2020; 34: 101536
22. Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JGN, Weir EK. Mitochondrial metabolism, redox signaling and fusion: a mitochondrial ROS-HIF-1-alpha-Kv15 O2 sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol (2008) 294: H570-8.Doi: 10.1152/ajpheart.01324.2007.
23. Tuder RM, Davis LA, Graham BB. Targeting energetic metabolism: a new frontier in the pathogenesis and treatment of pulmonary hypertension. Am J Resp Crit Care Med (2012) 18.260-6. Doi: 10.1164/rccm.201108-1563PP.
24. Dasgupta A, Wu D, Tian L, et al. Mitochondria in the pulmonary vasculature in health and disease: oxygen—sensing, metabolism and dynamics. Compr Physiol 2020; 10: 713-765.
25. Xu D, Li Y, Zhang Bo, et al. Resveratrol alleviates hypoxic pulmonary hypertension via anti-inflammation and antioxidant pathways in rats. Int. J Med. Sci. 2016; 13: 942-954
26. Slingo M. Oxygen-sensing pathways and pulmonary circulation. J Physiol 2023; Doi: 10.1113/JP284591.
27. Young J, Williams D, Thompson R. Thin air, thick vessels: Historical and current perspectives on hypoxic pulmonary hypertension. Frontiers in Medicine 2019; 6: Doi: 10.3389
28. Shimoda L, Laurie S. HIF and pulmonary vascular responses to hypoxia. J Appl Physiol 1985; 116: 867-874.
29. Tuder R, Archer S, Dorfmuller P, et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D4-D12.
30. Dunham K, Wu D, Sykes E, et al. Hypoxic pulmonary vasoconstriction from molecular mechanisms to medicine. Chest 2017; 151: 181-192.
31. Yu B, Wang X, Xie F, et.al. The role of hypoxia-inducible factors in cardiovascular diseases. Pharmacol Ther 2022; Doi: 10.1016
32. Shen Y, Gonchoarova E, et al. Twisted HIF: revisiting smooth muscle HIF-1a signaling in pulmonary hypertension. AM J Physio Lung Cell Mol Physio. 315: L387-389
33. Pullamsetti S, Mamazhakypov A, Weissman N, et al. Hypoxia-inducible factor signaling in pulmonary hypertension. J Clin Invest 2020; 130: 5638-5651.
34. Liu J, Wang W, Wang L, et al. IL-33 initiates vascular remodeling in hypoxic pulmonary hypertension by up-regulating HIF-1a and VEGF expression in vascular endothelial cells. EBioMedicine 2018; 33: 196-210.
35. Archer S, Gomberg-Maitland M, Maitland M, et al. Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 o2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 2008; 2194: H570-8.
36. Tian L, Wu D, Dasgupta A, et al. Epigenetic metabolic reprogramming of right ventricular fibroblasts in pulmonary arterial hypertension: A pyruvate dehydrogenase kinase-dependent shift in mitochondrial metabolism promotes right ventricular fibrosis. Circ Res 2020; 126: 1723-1745.
37. Mathew R. Inflammation and pulmonary hypertension. Cardiol Rev 2010; 18: 67-72.
38. D'Alessandro A, Kasmi K, Plecita-Hiavata L, et al. Hallmarks of pulmonary hypertension: Mesenchymal and inflammatory cell metabolic reprogramming. Antioxidants & Redox Signaling 2018; 28: Doi: 10.1089/ars.2017.7217
39. Luo Y, Teng X, Zhang L, et al. CD146-HIF-1a hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension. Nature Communication 2019; 10: 3551.
40. Christou H, Khalil R. Mechanisms of pulmonary vascular dysfunction in pulmonary hypertension and implications for novel therapies. Am J Physiol Heart Circ Physiol 2022; 322: H702-H724.
41. Yu Z, Xiao J, Chen X, et al. Bioactivities and mechanisms of natural medicines in the management of pulmonary arterial hypertension. Chinese Medicine 2022; 17: 13
42. Xu W, Erzurum S. Endothelia cell energy metabolism, proliferation, and apoptosis in pulmonary hypertension. Compr Physiol 2011; 1: 357-272