High Altitude Pulmonary Edema (HAPE) is a form of altitude illness that develops in travellers on rapid ascent to or physical exertion at altitudes (> 2500 m; 8200 ft) 1,2. The altitude, speed and mode of ascent and, above all, individual susceptibility are the most important determinants for the occurrence of HAPE. It commonly strikes the second night at a new altitude and rarely occurs after more than 4 days at a given altitude, owing to adaptive cellular and biochemical changes in pulmonary vessels 1,2. Briefly, HAPE is characterized by hypoxia-induced pulmonary hypertension (PH), oxygen sensing redox switches and intravascular over perfusion 1-4 .
Prolonged exposure to HA increases oxidative damage, which could be the consequence of increased reactive oxygen species (ROS), decreased antioxidants and free radical-mediated reduction in pulmonary NO bioavailability 4,5. Ladakhi highlanders, living for several thousand years at such a great height have adapted mechanisms different from lowlanders for combating oxidative stress, which is the most severe repercussion of HA 5,6 . Hence, the relevant pathways and its constituents that maintain redox balance become an important focus of attention. In this regard 8-iso prostaglandin F2α (8-isoPGF2α) is believed to be one of the most accurate markers to estimate oxidative stress, providing an important tool to explore the role of oxidative stress in the pathogenesis of human disease such as HAPE 3,5 .
Isoprostanes are prostaglandin(PG)-like substances that are produced in vivo independently of cyclooxygenase (COX) enzymes, mainly by free radical-induced peroxidation of arachidonic acid 7. The formation of PG-like compounds during auto-oxidation of polyunsaturated fatty acids was first reported in the mid-1970s, but isoprostanes were not discovered to be formed in vivo in humans until 1990 8 . F2-isoprostanes are a group of 64 compounds isomeric in structure to cyclooxygenase-derived PGF2 and one of the most important isoforms is 8-isoPGF2α 7,8. They are released in response to cellular activation; circulate in plasma and are excreted in the urine. Morrow et al. first described the non-enzymatic production of a series of prostaglandin-like compounds during peroxidation of membrane phospholipids by free radicals and reactive oxygen species. Further, isoprostanes, appear to act through tyrosine kinase, Rho, and Rho kinase (ROCK), leading to decreased activity of myosin light chain phosphatase (MLCP) 8 . The measurement of 8-iso-PGF2α in tissues and/or biological fluids provides a valuable approach to the quantification of oxidative stress as well as a biochemical basis for assessing therapeutic intervention, as there is tremendous increase in reactive oxygen species at hypobaric hypoxia thereby predisposing the healthy sojourners towards HAPE3 . Increased formation of 8-isoPGF2α has been detected in human cardiovascular diseases; it associates with enhanced plasma levels of noradrenaline and angiotensin II contributing to elevated vasoconstrictor effects and induces mitogenesis in vascular smooth muscle cells3,5 . Furthermore, 8-Isoprostaglandin concentration was found to be elevated in asthma, COPD 9 , cystic fibrosis (CF)10 and pulmonary sarcoidosis11. A considerable body of literature exists documenting an increased production of indicators of oxidative stress in breath, blood, urine and tissue of laboratory rats in response to hypoxia 3,12-13 .
In conclusion, increased 8-iso-PGF2α level has been associated with oxidative stress and pulmonary stress that, in turn, contributes to endothelial dysfunction, which is vital in the development of HAPE. Thus, this molecule holds immense potential for providing a major improvement in the field of high altitude.
- Bärtsch P, Mairbäurl H, Maggiorini M, Swenson ER. Physiological aspects of high-altitude pulmonary edema.J Appl Physiol (1985). 2005;98(3):1101-10.
- Swenson ER, Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbäurl H, Bärtsch P. Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor. JAMA 2002;287:2228-35.
- Mishra A, Ali Z, Vibhuti A, Kumar R, Alam P, Ram R, Thinlas T, Mohammad G, Pasha MA. CYBA and GSTP1 variants associate with oxidative stress under hypobaric hypoxia as observed in high-altitude pulmonary oedema. Clin Sci (Lond). 2012;122(6):299-309.
- Bailey DM, Dehnert C, Luks AM, Menold E, Castell C, Schendler G, Faoro V, Gutowski M, Evans KA, Taudorf S, James PE, McEneny J, Young IS, Swenson ER, Mairbäurl H, Bärtsch P, Berger MM.
- Ali Z, Waseem M, Kumar R, Pandey P, Mohammad G, Qadar Pasha MA. Unveiling the interactions among BMPR-2, ALK-1 and 5-HTT genes in the pathophysiology of HAPE. Gene. 2016 22;588(2):163-72.
- Pasha MA, Newman JH. High-altitude disorders: pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest. 2010;137(6 Suppl):13S-19S.
- Roberts LJ, Morrow JD. Measurement of F(2)-isoprostanes as an index of oxidative stress in vivo. Free Radic Biol Med. 2000 15;28(4):505-13.
- Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts LJ 2nd. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci USA. 1990;87(23):9383-7.
- Biernacki WA, Kharitonov SA, Barnes PJ. Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD. Thorax. 2003;58(4):294-8.
- Jefferson JA, Simoni J, Escudero E, Hurtado ME, Swenson ER, Wesson DE, Schreiner GF, Schoene RB, Johnson RJ, Hurtado A. Increased oxidative stress following acute and chronic high altitude exposure. High Alt Med Biol. 2004;5(1): 61-9.
- Montuschi P, Kharitonov SA, Ciabattoni G, Corradi M, van Rensen L, Geddes DM, Hodson ME, Barnes PJ.Exhaled 8-isoprostane as a new non-invasive biomarker of oxidative stress in cystic fibrosis. Thorax. 2000;55(3):205-9.
- Psathakis K, Papatheodorou G, Plataki M, Panagou P, Loukides S, Siafakas NM, Bouros D.8-Isoprostane, a marker of oxidative stress, is increased in the expired breath condensate of patients with pulmonary sarcoidosis.Chest. 2004;125(3):1005-11.
- Askew EW. Work at high altitude and oxidative stress: antioxidant nutrients.Toxicology. 2002 15;180(2):107-19.