Functional changes in the microvasculature accompany the conspicuous morphological changes in blood vessel number, size, and architecture.The remodeled endothelial cells also avidly take up cationic liposomes and upregulate neurokinin receptors, leading to an unusual sensitivity to substance P not found in pathogenfree mice. When we initially examined this issue in infected rats, no significant increase in beta-Alanine baseline leakage was detected. By using a more Xylazine sensitive approach, we found that the microvasculature of the infected tracheal mucosa is indeed leakier than normal under baseline conditions in the absence of other stimuli. Several factors are likely to participate in the leakiness of remodeled blood vessels.An increase in endothelial permeability resulting from focal separations nm in diameter between endothelial cells is likely to be involved. The increase in the lumenal surface area created by angiogenesis and microvascular enlargement would add to the leakage.In addition, the enlargement of arterioles may lower upstream resistance and increase the transmural driving force for leakage.Impaired clearance of extravasated proteins via lymphatics could be another factor, although this has not been documented experimentally.In normal vessels, histamine, bradykinin, substance P, and hydroxytryptamine. However, endothelial gaps may not be the only route for extravasation in remodeled vessels.Endothelial fenestrae, transcytotic vesicles, vesiculovacuolar organelles, and monolayer defects all may contribute to increased plasma extravasation in pathological conditions accompanied by angiogenesis and microvascular remodeling. The size and other biophysical properties of each route across the endothelium would determine the size of molecules or particles affected, but the relative contributions of these factors have been difficult to quantify.The largest route for leakage, a pathway that can accommodate particles min diameter, results from defects in the endothelial monolayer of tumor vessels, but similar defects have not been described in airway inflammation.In particular, substance P and the sensory nerve irritant capsaicin trigger an abnormally large amount of plasma leakage in the airways of infected rats. This vascular hyperreactivity is due to an increase in the expression of NK receptors on endothelial cells of the remodeled vessels. The hyperreactivity appears to be specific to substance P and other NK receptor agonists, as leakage produced by plateletactivating factor. Tissue stained by esterase histochemistry to demonstrate regions of abundant mucosal lymphoid tissue. These agents are commonly used in the treatment of chronic airway disease and are known to inhibit plasma leakage evoked by a variety of stimuli including antigen, substance P, bradykinin, and PAF. Doseresponse studies have shown that this treatment significantly reduces baseline leakage in infected rats.The reduction occurs at the same dosage of salmeterol that abolishes ovalbumininduced latephase leakage and S AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL leukocyte adhesion in pathogenfree rats. A h delay after treatment is necessary to achieve maximal inhibition because of the relatively slow onset but prolonged action of salmeterol, which completely eliminates the latephase leakage after allergen, reduces baseline leakage in airways of infected rats by. The inhibitory effect of salmeterol on plasma leakage is thought to be mediated by receptors because it is blocked by prior administration of the receptor antagonist ICI.