Pathogenesis of high-altitude pulmonary oedema: direct evidence of stress failure of pulmonary capillaries

Abstract

The pathogenesis of high-altitude pulmonary oedema (HAPE) is disputed. Recent reports show a strong correlation between the occurrence of HAPE and pulmonary artery pressure, and it is known that the oedema is of the high-permeability type. We have, therefore, proposed that HAPE is caused by ultrastructural damage to pulmonary capillaries as a result of stress failure of their walls. However, no satisfactory electron microscopy studies are available in patients with HAPE, and animal models are difficult to find. Madison strain Sprague-Dawley rats show a brisk pulmonary pressure response to acute hypoxia and are susceptible to HAPE. We exposed 13 Madison rats to a pressure of 294 torr for up to 12.5 h, or 4 rats to 236 torr for up to 8 h. Pulmonary arterial or right ventricular systolic pressures measured with a catheter increased from 30.5 +/- 0.5 (SEM) in controls (n = 4) to 48 +/- 2 torr (n = 11). The lungs were fixed for electron microscopy with intravascular glutaraldehyde. Frothy bloodstained fluid was seen in the trachea of three animals. Ultrastructural examination showed evidence of stress failure of pulmonary capillaries, including disruption of the capillary endothelial layer, or all layers of the wall, swelling of the alveolar epithelial layer, red blood cells (RBCs) and oedematous fluid in the alveolar wall interstitium, proteinaceous fluid and RBCs in the alveolar spaces, and fluid-filled protrusions of the endothelium into the capillary lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

The Oxygen Cascade from Atmosphere to Mitochondria as a Tool to Understand the (Mal)adaptation to Hypoxia

“…The thickness of the basal lamina, a layer of extracellular matrix formed by epithelial cells that acts as an attachment point for cells, may constitute a major resistance element in the pulmonary blood–gas barrier, representing a compromise between two needs: to provide mechanical resistance against excessive pressure and to facilitate gas diffusion across the alveolar barrier [ 229 ]. This compromise may break in pulmonary pathologies linked to hypoxia-induced pulmonary edema due to stress failure of pulmonary capillaries in PH [ 230 ] as well as in COPD [ 231 ]. Experimental data obtained in rats exposed to 5900 m/10.0 %O 2 for 2 weeks show that the thickness of the basal lamina nearly doubles, but this increase is efficiently prevented by phosphodiesterase 5 inhibitors in parallel with other parameters highlighting the development of PH and right-heart failure [ 232 ].…”

The pathophysiology of high altitude pulmonary edema

“…Mechanical injury to pulmonary endothelial cells, in the setting of elevated pulmonary artery pressures and overperfusion, may be caused by several mechanisms, including stretching of endothelial cell intercellular junctions and pores, shear stress from increased velocity of blood flow as proposed by Staub [16], or stress failure secondary to increased capillary transmural pressure as proposed by West et al [17]. Any of these mechanical causes of endothelial cell injury could result in increased capillary permeability.…”

Review of Pugh paper—a commentary

“…In fact, this is a clue to the pathogenesis of HAPE, where, as Hultgren originally suggested, there is apparently uneven hypoxic pulmonary vasoconstriction. We have proposed that capillaries that are exposed to high pressures develop damage to their walls, leading to the development of a high-permeability type of pulmonary edema [12].…”