Hypoxia causes permeability oedema in the constant-pressure perfused rat lung

Abstract

Alveolar hypoxia causes pulmonary oedema associated with increased lung capillary pressure and decreased alveolar fluid reabsorption. However, the role of altered permeability is unclear. The aim of the present study was to test whether hypoxia affects alveolar permeability and induces pulmonary oedema in rat lungs, and whether terbutaline affects oedema formation.Isolated lungs of normoxic rats were perfused at a constant pressure (12 cmH 2 O) and exposed to different levels of oxygenation (1.5-35% O 2 ). Terbutaline (10 -5 M) was applied as an aerosol or with the perfusate. Online measurements indicate an earlier onset of weight gain with an increasing degree of hypoxia and a shortened lung survival time (35% O 2 : ,220 min; 1.5% O 2 : ,120 min).Terbutaline did not prevent oedema formation in hypoxic lungs. The terbutaline-induced formation of cyclic adenosine monophosphate was decreased by 50% in hypoxia (1.5% O 2 ). In experiments terminated after 75 min, bronchoalveolar lavage fluid of hypoxic lungs contained protein that originated from perfusate indicating alveolar leakage. Since lactate dehydrogenase in perfusate was not increased at the onset of oedema formation, cell damage does not explain the increased permeability.In conclusion, these results indicate the formation of a leak for macromolecules of the isolated perfused rat lung, which is accelerated by hypoxia and causes alveolar flooding even at low perfusion pressure at a rate that exceeds absorption even after stimulation with terbutaline.KEYWORDS: Beta-adrenergic agonists, capillary permeability, cyclic adenosine monophosphate, hypoxia, pulmonary oedema P ulmonary oedema can occur in pathological situations that are directly or indirectly linked with alveolar hypoxia. High-altitude pulmonary oedema can be solely attributed to alveolar hypoxia. It occurs after rapid ascent to high altitude in a small percentage (,6%) of mountaineers [1]. In this situation, oedema formation is due to pulmonary hypertension and increased pulmonary capillary pressure [2]. Other possible mechanisms may include increased lung vascular endothelial and alveolar epithelial permeability [3,4] and inhibition of alveolar fluid reabsorption [1]. Evidence for the latter comes from the following: 1) prevention of high-altitude pulmonary oedema by inhalation of b-adrenergic agonists [5]; 2) terbutalineinduced stimulation of reabsorption of fluid instilled into lungs of hypoxia-exposed rats [6]; and 3) b-adrenergic stimulation of transepithelial sodium transport in primary rat alveolar epithelial cells [7].The significance of an increased capillary permeability in hypoxic oedema formation is not clear. Results from STELZNER et al.[3] on in vivo hypoxia of rats suggest an increase in permeability as indicated by an increase in pulmonary transvascular protein escape. Hypoxia, in combination with viral infection of the respiratory tract, increases the formation of pulmonary oedema and protein leak [8]. In humans exposed to highaltitude, permeability changes indicated by in...

Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability

“…In the lung, hypoxia is closely associated with a fall in intracellular cAMP levels (38) and results in suppression of epi-and endothelial barrier function, leading to pulmonary edema (12,45). Since IMD is upregulated by hypoxia and exerts profound stabilizing effects on endothelial barrier function both in cell culture and in the isolated, perfused lung, it might be part of a protective regulatory mechanism counteracting hypoxia-induced pulmonary edema.…”

Pathogenic Hantaviruses Direct the Adherence of Quiescent Platelets to Infected Endothelial Cells

“…Hantavirus patients are hypoxic, and high-altitude-induced pulmonary edema results from hypoxic conditions inducing VEGF (4,16,31,47). Since hypoxia-induced factor 1␣ (HIF1␣) induces VEGF and VEGF induces transcription of HIF1␣, an autocrine loop which amplifies endothelial cell permeability in response to hypoxia is formed (16,47,57,59).…”

“…A layer of platelets on the surfaces of endothelial cells may also alter capillary permeability by affecting gas exchange within vast pulmonary capillary beds and thereby contribute to a hypoxic state (4,16,57). Hantavirus patients are hypoxic, and high-altitude-induced pulmonary edema results from hypoxic conditions inducing VEGF (4,16,31,47).…”

Andes Virus Infection of Lymphatic Endothelial Cells Causes Giant Cell and Enhanced Permeability Responses That Are Rapamycin and Vascular Endothelial Growth Factor C Sensitive

“…VEGF-A induces the dissociation of VE-cadherin from interendothelial adherens junctions via a VEGFR2-Src-VE-cadherin signaling pathway and thereby regulates the primary fluid barrier of the endothelium (19,24,25,49). HPS patients are acutely hypoxic (36,39,59,62,79), suggesting a link between pulmonary edema during HPS and enhanced endothelial cell VEGF-A responses (12,15,16,38,57,64,76). In fact, both HTNV and ANDV enhance VEGF-A-directed permeability responses, and inhibitors that antagonize this pathway block the hyperpermeability of hantavirus-infected BECs (28,29,34,35,63).…”