Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Dec;82(6):1840–1847. doi: 10.1172/JCI113800

Hypoxia-induced increases in pulmonary transvascular protein escape in rats. Modulation by glucocorticoids.

T J Stelzner 1, R F O'Brien 1, K Sato 1, J V Weil 1
PMCID: PMC442762  PMID: 3198758

Abstract

Pulmonary edema after ascent to altitude is well recognized but its pathogenesis is poorly understood. To determine whether altitude exposure increases lung vascular permeability, we exposed rats to a simulated altitude of approximately 14,500 feet (barometric pressure [Pb] 450 Torr) and measured the pulmonary transvascular escape of radiolabeled 125I-albumin corrected for lung blood content with 51Cr-tagged red blood cells (protein leak index = PLI). Exposures of 24 and 48 h caused significant increases in PLI (2.30 +/- 0.08 and 2.40 +/- 0.06) compared with normoxic controls (1.76 +/- 0.06), but brief hypoxic exposures of 1-13 h produced no increase in PLI, despite comparable increases in pulmonary artery pressure. There were associated increases in gravimetric estimates of lung water in the altitude-exposed groups and perivascular edema cuffs on histologic examination. Normobaric hypoxia (48 h; fractional inspired oxygen concentration [FIO2] = 15%) also increased lung transvascular protein escape and lung water. Dexamethasone has been used to prevent and treat altitude-induced illnesses, but its mechanism of action is unclear. Dexamethasone (0.5 or 0.05 mg/kg per 12 h) started 12 h before and continued during 48 h of altitude exposure prevented the hypoxia-induced increases in transvascular protein escape and lung water. Hemodynamic measurements (mean pulmonary artery pressure and cardiac output) were unaffected by dexamethasone, suggesting that its effect was not due to a reduction in pulmonary artery pressure or flow. The role of endogenous glucocorticoid activity was assessed in adrenalectomized rats that showed augmented hypoxia-induced increases in transvascular protein escape, which were prevented by exogenous glucocorticoid replacement. In summary, subacute hypoxic exposures increased pulmonary transvascular protein escape and lung water in rats. Dexamethasone prevented these changes independent of reductions of mean pulmonary artery pressure or flow, whereas adrenalectomy increased pulmonary vascular permeability and edema at altitude. Increases in vascular permeability in hypoxia could contribute to the development of high-altitude pulmonary edema and endogenous glucocorticoids may have an important influence on pulmonary vascular permeability in hypoxia.

Full text

PDF
1840

Images in this article

1843Image
on p.1843
1843Image
on p.1843
1844Image
on p.1844

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bland R. D., Demling R. H., Selinger S. L., Staub N. C. Effects of alveolar hypoxia on lung fluid and protein transport in unanesthetized sheep. Circ Res. 1977 Mar;40(3):269–274. doi: 10.1161/01.res.40.3.269. [DOI] [PubMed] [Google Scholar]
  2. Dauber I. M., Pluss W. T., VanGrondelle A., Trow R. S., Weil J. V. Specificity and sensitivity of noninvasive measurement of pulmonary vascular protein leak. J Appl Physiol (1985) 1985 Aug;59(2):564–574. doi: 10.1152/jappl.1985.59.2.564. [DOI] [PubMed] [Google Scholar]
  3. Ellsworth A. J., Larson E. B., Strickland D. A randomized trial of dexamethasone and acetazolamide for acute mountain sickness prophylaxis. Am J Med. 1987 Dec;83(6):1024–1030. doi: 10.1016/0002-9343(87)90937-5. [DOI] [PubMed] [Google Scholar]
  4. Hansen T. N., Hazinski T. A., Bland R. D. Effects of asphyxia on lung fluid balance in baby lambs. J Clin Invest. 1984 Aug;74(2):370–376. doi: 10.1172/JCI111432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Heath D., Moosavi H., Smith P. Ultrastructure of high altitude pulmonary oedema. Thorax. 1973 Nov;28(6):694–700. doi: 10.1136/thx.28.6.694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Huber F., Sodal I. E., Weil J. V. On-line cardiac output by digital computer. J Appl Physiol. 1976 Feb;40(2):266–268. doi: 10.1152/jappl.1976.40.2.266. [DOI] [PubMed] [Google Scholar]
  7. Johansson B. Effect of dexamethasone on protein extravasation in the brain in acute hypertension induced by amphetamine. Acta Neurol Scand. 1978 Feb;57(2):180–185. doi: 10.1111/j.1600-0404.1978.tb02835.x. [DOI] [PubMed] [Google Scholar]
  8. Johnson T. S., Rock P. B., Fulco C. S., Trad L. A., Spark R. F., Maher J. T. Prevention of acute mountain sickness by dexamethasone. N Engl J Med. 1984 Mar 15;310(11):683–686. doi: 10.1056/NEJM198403153101103. [DOI] [PubMed] [Google Scholar]
  9. Kinasewitz G. T., Groome L. J., Marshall R. P., Leslie W. K., Diana J. N. Effect of hypoxia on permeability of pulmonary endothelium of canine visceral pleura. J Appl Physiol (1985) 1986 Aug;61(2):554–560. doi: 10.1152/jappl.1986.61.2.554. [DOI] [PubMed] [Google Scholar]
  10. Landolt C. C., Matthay M. A., Albertine K. H., Roos P. J., Wiener-Kronish J. P., Staub N. C. Overperfusion, hypoxia, and increased pressure cause only hydrostatic pulmonary edema in anesthetized sheep. Circ Res. 1983 Mar;52(3):335–341. doi: 10.1161/01.res.52.3.335. [DOI] [PubMed] [Google Scholar]
  11. Lockhart A., Saiag B. Altitude and the human pulmonary circulation. Clin Sci (Lond) 1981 Jun;60(6):599–605. doi: 10.1042/cs0600599. [DOI] [PubMed] [Google Scholar]
  12. Long J. B., Holaday J. W. Blood-brain barrier: endogenous modulation by adrenal-cortical function. Science. 1985 Mar 29;227(4694):1580–1583. doi: 10.1126/science.3975627. [DOI] [PubMed] [Google Scholar]
  13. Maresh C. M., Noble B. J., Robertson K. L., Harvey J. S., Jr Aldosterone, cortisol, and electrolyte responses to hypobaric hypoxia in moderate-altitude natives. Aviat Space Environ Med. 1985 Nov;56(11):1078–1084. [PubMed] [Google Scholar]
  14. Martin D. J., Grimbert F. A., Baconnier P., Benchetrit G. Effect of acute hypoxia on lung transvascular filtration in anaesthetized dogs. Bull Eur Physiopathol Respir. 1983 Jan-Feb;19(1):7–11. [PubMed] [Google Scholar]
  15. PEARCE M. L., YAMASHITA J., BEAZELL J. MEASUREMENT OF PULMONARY EDEMA. Circ Res. 1965 May;16:482–488. doi: 10.1161/01.res.16.5.482. [DOI] [PubMed] [Google Scholar]
  16. Parker R. E., Granger D. N., Taylor A. E. Estimates of isogravimetric capillary pressures during alveolar hypoxia. Am J Physiol. 1981 Nov;241(5):H732–H739. doi: 10.1152/ajpheart.1981.241.5.H732. [DOI] [PubMed] [Google Scholar]
  17. Reeves J. T., Wagner W. W., Jr, McMurtry I. F., Grover R. F. Physiological effects of high altitude on the pulmonary circulation. Int Rev Physiol. 1979;20:289–310. [PubMed] [Google Scholar]
  18. Schoene R. B. Pulmonary edema at high altitude. Review, pathophysiology, and update. Clin Chest Med. 1985 Sep;6(3):491–507. [PubMed] [Google Scholar]
  19. Scott K. W., Barer G. R., Leach E., Mungall I. P. Pulmonary ultrastructural changes in hypoxic rats. J Pathol. 1978 Sep;126(1):27–33. doi: 10.1002/path.1711260104. [DOI] [PubMed] [Google Scholar]
  20. Sobin S. S., Tremer H. M., Hardy J. D., Chiodi H. P. Changes in arteriole in acute and chronic hypoxic pulmonary hypertension and recovery in rat. J Appl Physiol Respir Environ Exerc Physiol. 1983 Nov;55(5):1445–1455. doi: 10.1152/jappl.1983.55.5.1445. [DOI] [PubMed] [Google Scholar]
  21. Staub N. C. Pulmonary edema due to increased microvascular permeability to fluid and protein. Circ Res. 1978 Aug;43(2):143–151. doi: 10.1161/01.res.43.2.143. [DOI] [PubMed] [Google Scholar]
  22. Stelzner T. J., Welsh C. H., Berger E., McCullough R. G., Morris K., Repine J. E., Weil J. V. Antiarrhythmic agents diminish thiourea-induced pulmonary vascular protein leak in rats. J Appl Physiol (1985) 1987 Nov;63(5):1877–1883. doi: 10.1152/jappl.1987.63.5.1877. [DOI] [PubMed] [Google Scholar]
  23. Sugita T., Hyers T. M., Dauber I. M., Wagner W. W., McMurtry I. F., Reeves J. T. Lung vessel leak precedes right ventricular hypertrophy in monocrotaline-treated rats. J Appl Physiol Respir Environ Exerc Physiol. 1983 Feb;54(2):371–374. doi: 10.1152/jappl.1983.54.2.371. [DOI] [PubMed] [Google Scholar]
  24. Welsh C. H., Dauber I. M., Weil J. V. Endotoxin increases pulmonary vascular protein permeability in the dog. J Appl Physiol (1985) 1986 Oct;61(4):1395–1402. doi: 10.1152/jappl.1986.61.4.1395. [DOI] [PubMed] [Google Scholar]
  25. Whayne T. F., Jr, Severinghaus J. W. Experimental hypoxic pulmonary edema in the rat. J Appl Physiol. 1968 Dec;25(6):729–732. doi: 10.1152/jappl.1968.25.6.729. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES