Pulmonary capillary endothelial dysfunction in early systemic sclerosis

Abstract

Objective Pulmonary capillary endothelium–bound angiotensin‐converting enzyme (PCEB‐ACE) activity is a sensitive and quantifiable index of endothelial function in vivo. Systemic sclerosis (SSc) is characterized by endothelial damage and excess collagen formation, causing mainly pulmonary hypertension (PH) in the limited cutaneous SSc (lcSSc) subset and interstitial lung disease with pulmonary interstitial fibrosis (PIF) in the diffuse cutaneous SSc (dcSSc) subset. This study was undertaken to investigate the hypothesis that PCEB‐ACE activity is reduced early in SSc, in the absence of PH or PIF. Methods Applying indicator‐dilution techniques, we measured single‐pass transpulmonary hydrolysis and percent metabolism (%M) of a synthetic ACE substrate and calculated functional capillary surface area (FCSA) in 25 SSc patients and 11 controls. Substrate hydrolysis and %M reflect ACE activity per capillary; FCSA reflects ACE activity per vascular bed. Results PCEB‐ACE activity was decreased in both SSc subsets. Among patients without PH, substrate hydrolysis and %M were decreased in patients with lcSSc and more profoundly in those with dcSSc; loss of FCSA normalized to body surface area (FCSA/BSA) was observed in dcSSc, but not in lcSSc. High‐resolution computed tomography of the lung, performed in all SSc patients, revealed no correlation between substrate %M, hydrolysis, or FCSA/BSA and the degree of PIF; 5 dcSSc and 5 lcSSc patients with no detectable PIF exhibited decreases in hydrolysis and %M, while FCSA/BSA was decreased only in dcSSc. Conclusion Depression of PCEB‐ACE activity, indicating pulmonary endothelial dysfunction, occurs early in SSc, in the absence of PH or PIF, and is more pronounced, at this early pulmonary disease stage, in dcSSc than in lcSSc.

The Angiotensin-Converting Enzyme 2/Angiogenesis-(1–7)/Mas Axis Confers Cardiopulmonary Protection against Lung Fibrosis and Pulmonary Hypertension

“…Lung protein analysis revealed decreased ACE levels in bleomycin-treated rats. Decreased pulmonary ACE activity associated with bleomycin injury has been reported in both animal and human studies (31)(32)(33), which confirm our current findings.…”

Endothelial pathomechanisms in acute lung injury

“…In a similar respect, PCEB-ACE activity was assessed in patients undergoing total knee arthroplasty; enzyme activity depression occurred in association to lung injury induction secondary to embolic lung syndrome (Jules-Elysee et al, 2004). In addition to the aforementioned PCEB-ACE activity reductions seen in acute lung vascular pathologies, enzyme activity depressions appear to occur in chronic lung vasculopathies related to systemic sclerosis and pulmonary arterial hypertension (Langleben et al, 2008;Orfanos et al, 2001).…”

Biomarkers of Scleroderma Lung Disease: Recent Progress

“…Endothelial cell injury is widespread in SSc, including in the pulmonary capillary endothelium. Functional studies indicate the presence of pulmonary capillary endothelial dysfunction prior to the occurrence of pulmonary fibrosis (PF) or pulmonary hypertension [9]. 99m Tc-DTPA (diethylene triamine pentaacetic acid) clearance scans demonstrate increased radionuclide clearance consistent with an abnormality at the alveolar epithelial cell barrier [10].…”