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

• Published in: American journal of physiology. Renal physiology Vol. 314; no. 2; p. F203
• Main Authors: Khatib-Massalha, Eman, Michelis, Regina, Trabelcy, Beny, Gerchman, Yoram, Kristal, Batya, Ariel, Amiram, Sela, Shifra
• Format: Journal Article
• Language: English
• Published: United States 01-02-2018
• Subjects: Adult; Aged; Aged, 80 and over; alpha 1-Antitrypsin - blood; Biomarkers - blood; Case-Control Studies; Chronic Disease; Female; Humans; Inflammation - blood; Inflammation - diagnosis; Inflammation - enzymology; Inflammation - etiology; Inflammation Mediators - blood; Kidney Failure, Chronic - blood; Kidney Failure, Chronic - diagnosis; Kidney Failure, Chronic - enzymology; Kidney Failure, Chronic - therapy; Leukocyte Elastase - blood; Leukocyte Elastase - genetics; Male; Middle Aged; Neutrophil Activation; Neutrophils - enzymology; Renal Dialysis - adverse effects; Treatment Outcome; Up-Regulation; polymorphonuclear leukocytes; PMNLs; inflammation; PMNL priming; PMNL elastase
• ISSN: 1522-1466
• DOI: 10.1152/ajprenal.00070.2017

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.