Pulmonary ischemia/reperfusion injury: A quantitative study of structure and function in isolated heart-lungs of the rat

Early graft dysfunction after lung transplantation is a significant and unp redictable problem. Our study aimed at a detailed investigation of structur e-function correlations in a rat isolated heart-lung model of ischemia/repe rfusion injury. Variable degrees of injury were induced by preservation with potassium-modi fied Euro-Collins solutions, 2 hr of cold ischemia, and 40 min of reperfusi on. Pulmonary artery pressure (P-pa), pulmonary vascular resistance (PVR), peak inspiratory pressure (PIP), and perfusate gases (Delta P-O2, Delta P-C O2) were recorded during reperfusion. Right lungs were used to calculate W/ D-weight ratios. Nineteen experimental and six control left lungs were fixe d for light and electron microscopy by vascular perfusion. Systematic rando m samples were analyzed by stereology to determine absolute and relative vo lumes of lung structures, the amount of interstitial and intraalveolar edem a, and the extent of epithelial injury. Lectin- and immunohistochemistry us ing established epithelial cell markers were performed in three animals per group to reveal sites of severe focal damage. Experimental lungs showed a wide range in severity of ischemia/reperfusion injury. Intraalveolar edema fluid amounted to 77-909 mm(3) with a mean of 4 48 +/- 250 mm(3) as compared with 22 +/- 22 mm(3) in control lungs (P < 0.0 01). Perfusate oxygenation (Delta P-O2) decreased from 30.5 +/- 15.2 to 21. 7 +/- 15.2 mm Hg (P = 0.05) recorded after 5 and 40 minutes of reperfusion. In experimental lungs, a surface fraction of 1% to 58% of total type I pne umocyte surface was damaged. Intraalveolar edema per gas exchange region (V v ape,P) and Delta P-O2 were related according to Delta P-O2 = 96 - 60 x lo g(10)(Vv ape,P) [mm Hg]. The extent of epithelial injury did not correlate with Delta P-O2, nor with intraalveolar edema, but increased significantly with PVR. Lectin- and immunohistochemistry revealed focal severe damage to the alveolar epithelium at the border of perivascular cuffs. We conclude that ischemia/reperfusion-associated respiratory compromise is a direct function of the amount of intraalveolar edema, however, it is not determined by the actual extent of diffuse alveolar epithelial damage at th e air-blood-barrier but by the presence of focal severe epithelial damage a t the perivascular/alveolar interface. (C) 1999 Wiley-Liss, Inc.