Lungs and hypoxia: a review of the literature

Abstract

Acute, intermittent or chronic hypoxia have negative effects on lung maturation during the embryological period which has been shown by many experimental models designed on animal studies. The receptors responsible from the development of lungs in fetal period are affected from hypoxia. Hypoxia also affects the morphometry, anatomy and microscopy of lung tissue in the adults. In acute phase of hypoxia; lung parenchyma showed destructive oxidative changes. However, in later phases repair and proliferative processes were observed in the lung tissue. Damage to the lining layer of alveoli, accumulation of alveolar macrophages, oedematous changes in the lung parenchyma, mild oedema, inflammatory cell infiltration, increased number of type II pneumocytes and pulmonary fibrosis are the main findings in cases of hypoxia. Chronic hypoxia accentuates lung growth by increasing the lung parenchyma. Decrease of capillary volume and suppression of elastin repair in lung fibroblasts are other clinically important microscopic findings in hypoxia. Many molecular studies found in the literature revealed micro-RNAs to be involved in modulation of hypoxia-induced pulmonary hypertension. In animal models submitted to acute hypobaric hypoxia; the researchers detected an increase in eNOS mRNA which is responsible of the immediate response, producing nitric oxide that caused vasodilation and bronchodilation in lung tissue. In other molecular studies; suppression of many immune molecules, major changes at the levels of various enzymes and growth factors were detected in the researches. Additionally; hypoxia causes to an increase in the amount of lung cancer cells and therefore; induces the metastases of lung cancer cells to brain tissues.

Keywords

• cancer
• gross anatomy
• hypoxia
• lung
• microscopy
• molecular study

Project Number

YOK

References

1. Saladin KS. Anatomy and physiology. The unity of form and function. 8th ed. New York (NY): Mc Graw Hill Education; 2018. 878 p.
2. Tuder RM, Yun JH, Bhunia A, Fijalkowska I. Hypoxia and chronic lung disease. J Mol Med 2007;85:1317–24.
3. Schwartz JE, Kovach A, Meyer J, McConnell C, Iwamoto HS. Brief, intermittent hypoxia restricts fetal growth in Sprague-Dawley rats. Biol Neonate 1998;73:313–19.
4. Van Tuyl M, Liu J, Wang J, Kuliszewski M, Tibboel D, Post M. Role of oxygen and vascular development in epithelial branching morphogenesis of the developing mouse lung. Am J Physiol Lung Cell Mol Physiol 2005;288:L167–78.
5. Tufro-McReddie A, Norwood VF, Aylor KW, Botkin SJ, Carey RM, Gomez RA. Oxygen regulates vascular endothelial growth factor-mediated vasculogenesis and tubulogenesis. Dev Biol 1997;2: 139–49.
6. Maltepe E, Simon MC. Oxygen, genes, and development: an analysis of the role of hypoxic gene regulation during murine vascular development. J Mol Med (Berl) 1998;6:391–401.
7. Groenman FA, Rutter M, Wang J, Caniggia I, Tibboel D, Post M. Effect of chemical stabilizers of hypoxia-inducible factors on early lung development. Am J Physiol Lung Cell Mol Physiol 2007;3: L557–67.
8. Zhang H, Burggren WW. Hypoxic level and duration differentially affect embryonic organ system development of the chicken (Gallus gallus). Poult Sci 2012;91:3191–201.

9. Schmiedl A, Roolfs T, Tutdibi E, Gortner L, Monz D. Influence of prenatal hypoxia and postnatal hyperoxia on morphologic lung maturation in mice. PLoS One 2017;12:e0175804.
10. Davies P, Maddalo F, Reid L. Effects of chronic hypoxia on structure and reactivity of rat lung microvessels. J Appl Physiol 1985;58: 795–801.
11. Sekhon HS, Thurlbeck WM. Lung morphometric changes after exposure to hypobaria and/or hypoxia and undernutrition. Respir Physiol 1996;106:99–107.
12. Sulkowska M. Morphological studies of the lungs in chronic hypobaric hypoxia. Pol J Pathol 1997;48:225–34.
13. Clough AV, Haworth ST, Ma W, Dawson CA. Effects of hypoxia on pulmonary microvascular volume. Am J Physiol Heart Circ Physiol 2000;279:H1274–82.
14. Gade J, Qvortrup K, Andersen CB, Thorsen S, Svendsen UG, Olsen PS. Bronchial arterial devascularization. An experimental study in pigs. Scand Cardiovasc J 2001;35:212–20.
15. Gade J, Greisen G, Larsen IK, Bibby BM, Olsen PS. Tissue hypoxaemia causes oedema, inflammation and fibrosis in porcine bronchial transection. Scand Cardiovasc J 2012;46:286–94.
16. Berk JL, Hatch CA, Morris SM, Stone PJ, Goldstein RH. Hypoxia suppresses elastin repair by rat lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2005;289:L931–6.
17. Miserocchi G. Lung interstitial pressure and structure in acute hypoxia. Adv Exp Med Biol 2007;618:141–57.
18. Reinke C, Bevans-Fonti S, Grigoryev DN, Drager LF, Myers AC, Wise RA, Schwartz AR, Mitzner W, Polotsky VY. Chronic intermittent hypoxia induces lung growth in adult mice. Am J Physiol Lung Cell Mol Physiol 2011;300:L266–73.
19. Zhang X, Xie M, Gao Y, Wei HH, Zheng JQ. Study on the effect and mechanism of hypoxia on the histological structure of rat’s lung [Article in Chinese]. Sichuan Da Xue Xue Bao Yi Xue Ban 2012;43: 1–5.
20. Llapur CJ, Martínez MR, Grassino PT, Stok A, Altieri HH, Bonilla F, Caram MM, Krowchuk NM, Kirby M, Coxson HO, Tepper RS. Chronic hypoxia accentuates dysanaptic lung growth. Am J Respir Crit Care Med 2016;194:327–32.
21. Rivolta I, Lucchini V, Rocchetti M, Kolar F, Palazzo F, Zaza A, Miserocchi G. Interstitial pressure and lung oedema in chronic hypoxia. Eur Respir J 2011;37:943–9.
22. Brinkmann B. Vital reactions of the pulmonary circulation in fatal strangulation. Z Rechtsmed 1978;81:133–46.
23. Brinkmann B, Püschel K. Histomorphological alterations of lung after strangulation. A comparative experimental study. Z Rechtsmed 1981;86:175–94.
24. Du Chesne A, Cecchi-Mureani R, Püschel K, Brinkmann B. Macrophage subtype patterns in protracted asphyxiation. Int J Legal Med 1996;109:163–6.
25. Strunk T, Hamacher D, Schulz R, Brinkmann B. Reaction patterns of pulmonary macrophages in protracted asphyxiation. Int J Legal Med 2010;124:559–68.
26. Muciaccia B, Sestili C, De Grossi S, Vestri A, Cipolloni L, Cecchi R. Are mast cells implicated in asphyxia? Int J Legal Med 2016;130: 153–61.
27. Orth T, Allen JA, Wood JG, Gonzalez NC. Plasma from conscious hypoxic rats stimulates leukocyte-endothelial interactions in normoxic cremaster venules. J Appl Physiol (1985) 2005;99:290–7.
28. Urquhart DS, Montgomery H, Jaffé A. Assessment of hypoxia in children with cystic fibrosis. Arch Dis Child 2005;90:1138–43.
29. Tzouvelekis A, Harokopos V, Paparountas T, Oikonomou N, Chatziioannou A, Vilaras G, Tsiambas E, Karameris A, Bouros D, Aidinis V. Comparative expression profiling in pulmonary fibrosis suggests a role of hypoxia-inducible factor-1alpha in disease pathogenesis. Am J Respir Crit Care Med 2007;176:1108–19.
30. Ahmedat A, Warnken M, Seemann W, Mohr K, Kostenis E, Juergens U, Racké K. Profibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system. Br J Pharmacol 2013;168:471–87.
31. Ge L, Ming T, Hou J, Yan J, Zhao L, Gong N, Jiang J, Wang F. Pathological changes of upper and lower respiratory tissue in rats with chronic intermittent hypoxia [Article in Chinese]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi (Chinese Journal of Otorhinolaryngology Head and Neck Surgery) 2015;50:939–43.
32. Liu SS, Wang HY, Tang JM, Zhou XM. Hypoxia-induced collagen synthesis of human lung fibroblasts by activating the angiotensin system. Int J Mol Sci 2013;14:24029–45.
33. Tsao PN, Wei SC. Prenatal hypoxia downregulates the expression of pulmonary vascular endothelial growth factor and its receptors in fetal mice. Neonatology 2013;103:300–7.
34. Sturrock A, Woller D, Freeman A, Sanders K, Paine R. Consequences of hypoxia for the pulmonary alveolar epithelial cell innate immune response. J Immunol 2018;201:3411–20.
35. Li Q, Zhou X, Zhou X. Downregulation of miR 98 contributes to hypoxic pulmonary hypertension by targeting ALK1. Mol Med Rep 2019;20:2167–76.
36. Liu T, Zou XZ, Huang N, Ge XY, Yao MZ, Liu H, Zhang Z, Hu CP. miR-27a promotes endothelial-mesenchymal transition in hypoxia-induced pulmonary arterial hypertension by suppressing BMP signaling. Life Sci 2019;227:64–73.
37. Liu A, Liu Y, Li B, Yang M, Liu Y, Su J. Role of miR-223-3p in pulmonary arterial hypertension via targeting ITGB3 in the ECM pathway. Cell Prolif 2019;52:e12550.
38. Blissenbach B, Nakas CT, Krönke M, Geiser T, Merz TM, Pichler Hefti J. Hypoxia-induced changes in plasma micro-RNAs correlate with pulmonary artery pressure at high altitude. Am J Physiol Lung Cell Mol Physiol 2018;314:L157–64.
39. Martínez-Romero R, Cañuelo A, Siles E, Oliver FJ, Martínez-Lara E. Nitric oxide modulates hypoxia-inducible factor-1 and poly (ADP-ribose) polymerase-1 cross talk in response to hypobaric hypoxia. J Appl Physiol 2012;112:816–23.
40. Singh M, Yadav S, Kumar M, Saxena S, Saraswat D, Bansal A, Singh SB. The MAPK-activator protein-1 signaling regulates changes in lung tissue of rat exposed to hypobaric hypoxia. J Cell Physiol 2018;233:6851–65.
41. Rus A, Peinado MA, Castro L, Del Moral ML. Lung eNOS and iNOS are reoxygenation time-dependent upregulated after acute hypoxia. Anat Rec 2010;293:1089–98.
42. Rus A, Molina F, Peinado MA, Del Moral ML. Endogenous nitric oxide can act as beneficial or deleterious in the hypoxic lung depending on the reoxygenation time. Anat Rec 2010;293:2193– 201.
43. Chen A, Sceneay J, Gödde N, Kinwel T, Ham S, Thompson EW, Humbert PO, Möller A. Intermittent hypoxia induces a metastatic phenotype in breast cancer. Oncogene 2018;37:4214–25.
44. Wei DF, Tang MK, Liu Y, Zhang CY, Qin LJ. Effect of hypoxia inducible Factor-1 alpha on brain metastasis from lung cancer and its mechanism [Article in Chinese]. Sichuan Da Xue Xue Bao Yi Xue Ban 2019;50:188–92.