Free circulating active elastase contributes to chronic inflammation in patients on hemodialysis

Abstract

Atherosclerosis and cardiovascular complications are prevalent among patients undergoing chronic hemodialysis (HD). In this population, peripheral polymorphonuclear leukocytes (PMNLs) are primed, releasing proinflammatory mediators such as elastase. Elastase is normally inhibited by a specific inhibitor, avoiding undesirable degradation of cellular and extracellular components. This study tested the hypothesis that in states of noninfectious inflammation, elastase is released by PMNLs and acts in an uncontrolled manner to inflict vascular damage. Blood was collected from patients undergoing HD and healthy controls (HC). PMNL intracellular and surface expressions of elastase were determined by quantitative real-time PCR, Western blotting, and flow cytometry. The elastase activity was evaluated using a fluorescent substrate. The levels of serum α-antitrypsin (α-AT), the natural elastase inhibitor, were determined by Western blot. Free active elastase was elevated in HD sera, whereas the levels of α-AT were decreased compared with HC. The levels of the intracellular elastase enzyme and its activity were lower in HD PMNLs despite similar expression levels of elastase mRNA. Elastase binding to PMNL cell surface was higher in HD compared with HC. The increased circulating levels of free active elastase released from primed HD PMNLs together with the higher cell surface-bound enzymes and the lower levels of α-AT result in the higher elastase activity in HD sera. This exacerbated elastase activity could lead to the endothelial dysfunction, as hypothesized. In addition, it suggests that free circulating elastase can serve as a new biomarker and therapeutic target to reduce inflammation and vascular complications in patients on hemodialysis.

Neutrophil Elastase Inhibitors and Chronic Kidney Disease

“…Moreover, the elevated levels of elastase and cathepsin G, continuously released during hemodialysis session, can initiate vascular injury by cleavage of vascular endothelial cadherin in HD patients 128 . In line, it was reported that higher serum levels of free elastase, together with lower levels of AAT, contribute for the endothelial dysfunction 129 .…”

Neutrophil degranulation and severely impaired extracellular trap formation at the basis of susceptibility to infections of hemodialysis patients

“…The substantial neutrophil degranulation and intracellular reduction of key antibacterial proteins such as MPO, NE, and MMP-9 may result from persistent immune activation by uremia, the HD procedure, or the low-grade chronic inflammation seen in HD patients. Indeed, serum NE [ 48 ] and MPO [ 49 ] levels are highly elevated and correlate with levels of markers of inflammation and prospective mortality risk in HD patients. Moreover, MPO levels are significantly higher after HD than pre-dialysis levels, suggesting HD treatment “per se” can aggravate immune cell activation and degranulation [ 50 ].…”

Exploring the Link Between Hepatic Perfusion and Endotoxemia in Hemodialysis

“… 40 , 42 , 43 In addition, endotoxin itself has also been shown to induce oxidative stress 44 , 45 and attenuate ICG clearance. 46 , 47 Increased levels of these and other inflammatory mediators have been characterized in ESRD and HD patients, 3 , 44 , 45 , 48 , 49 , 50 , 51 suggesting that the liver is susceptible to recurrent HD-induced circulatory stress via inflammatory mediators which negatively affect hepatic function.…”