Pulmonary Capillary Endothelium-Bound Angiotensin-Converting Enzyme Activity in Humans

Abstract

Background-Pulmonary endothelium has metabolic functions including the conversion of angiotensin I to angiotensin II by angiotensin-converting ectoenzyme (ACE). In this study, we have validated an indicator-dilution technique that provides estimations of dynamically perfused capillary surface area (DPCSA) in humans, and we have characterized pulmonary endothelial ACE in vivo. Methods and Results-In 12 adults, single-pass transpulmonary (one or both lungs) hydrolysis of the specific ACE substrate 3 H-benzoyl-Phe-Ala-Pro ( 3 H-BPAP) was measured and expressed as % metabolism (%M) and vϭϪln(1ϪM). We also calculated A max /K m , an index of DPCSA. %M (70.1Ϯ3.2 vs 67.9Ϯ3.1) and v (1.29Ϯ0.14 vs 1.20Ϯ0.12) were similar in both lungs and the right lung, respectively, whereas A max /K m/ /body surface area decreased from 2460Ϯ193 to 1318Ϯ115 mL/min per square meter. Conclusions-Pulmonary endothelial ACE activity can be assessed in humans at the bedside by means of indicatordilution techniques. Our data suggest homogeneous pulmonary capillary ACE concentrations and capillary transit times (t c ) in both human lungs, and similar t c within the normal range of cardiac index. A max /K m in the right lung is 54% of total A max /K m in both lungs, suggesting that A max /K m is a reliable and quantifiable index of DPCSA in humans.

Factors modulating the delivery and effect of enzymatic cargo conjugated with antibodies targeted to the pulmonary endothelium

“…This study will present experiments that begin to define some of the biological factors and elements of DDS design that regulate the targeting and effects of an enzymatic cargo in the pulmonary vasculature, an important target for pharmacological interventions [1,3,15,16]. To achieve this goal, we utilized an enzyme (glucose oxidase, GOX, that generates H 2 O 2 from O 2 and glucose) as a model cargo coupled with well-characterized antibodies to an endothelial determinant enriched in the lungs, thrombomodulin (TM) [17].…”

Pulmonary capillary endothelial metabolic dysfunction: Severity in pulmonary arterial hypertension related to connective tissue disease versus idiopathic pulmonary arterial hypertension

“…The results for this control group have been published previously, in other studies in which these subjects also served as controls (8,9).…”

“…Nineteen patients with PAH-CTD (3 with diffuse systemic sclerosis, 9 with limited systemic sclerosis, 1 with systemic lupus erythematosus, 2 with mixed CTD, 1 with polymyositis, and 3 with rheumatoid arthritis) (15) and 25 patients with IPAH were studied. Partial data from 2 of the patients with IPAH and 3 of the patients with PAH-CTD were presented briefly as part of our initial validation study (8). The diagnoses were established and all patients were evaluated according to the recommendations of the third World Symposium on Pulmonary Arterial Hypertension (11).…”

“…Using indicatordilution-type techniques under first-order reaction conditions, we estimated the %M and the hydrolysis of BPAP and calculated the kinetic parameters of this reaction. This method provides estimates of pulmonary endothelial ACE activity in the microvessels, which is almost exclusively capillary-based (i.e., PCEB-ACE activity) (8,16,17). One milliliter of a 3 H-BPAP solution (30 Ci/1.2 ml of 0.9% saline, or 22.2 Ci/mmole) was used for each injection, followed by 5 ml of 0.9% saline flush.…”

“…We have previously validated measurements of PCEB-ACE activity and FCSA in subjects with healthy lungs, in patients with systemic sclerosis but no PAH, and in patients with acute lung injury (8)(9)(10). We have also previously evaluated the characteristics of PAH in a small number of patients, in order to demonstrate that reductions in PCEB-ACE activity are within the range of detection by this technique (8). There has, however, been no description of larger cohorts of patients with PAH and no analysis of variation between the types of PAH.…”