ULTRASTRUCTURAL-CHANGES OF LUNG CAPILLARY ENDOTHELIUM IN RESPONSE TO BOTULINUM C-2 TOXIN

The role of the endothelial cytoskeleton for the structural integrity of the pulmonary gas exchange area was probed with the use of Clostrid ium botulinum C-2 toxin. This agent causes selective loss of nonmuscle F-actin. In buffer-perfused rabbit lungs, vascular pressures were kep t within physiological ranges. In different groups, low-dose [0.3 (C-2 ,C-I)/0.6 (C-2,C-II) ng/ml] and high-dose [10 (C-2,C-I)/20 (C-2,C-II) ng/ml] toxin were applicated into the buffer fluid; experiments were t erminated after a total weight gain of either 1 or 7.5 g. Electron mic roscopy revealed extensive attenuations, undulations, and protrusions of the endothelial layer, suggestive of ''remodeling'' and ''flowing'' of the cell membrane in low C-2 toxin-treated lungs accompanied by fe w disruptions of the endothelial layer and edema formation. In additio n, endothelial cells displayed vesiculation and bleb formation. Lungs that were exposed to high-toxin doses displayed marked attenuations of the endothelial layer in addition to large endothelial cell disruptio ns, which did not include interendothelial junctions. Interestingly, t ype II epithelial cells displayed fusion of lamellar bodies. Collectiv ely, these data suggest that the actin microfilament system is instrum ental in supporting endothelial cell membrane configuration and integr ity and maintains the intimal barrier function of tile lung microvascu lature.