The autodigestion hypothesis: Proteolytic receptor cleavage in rheological and cardiovascular cell dysfunction1

Abstract

Transformation of circulating leukocytes from a dormant into an activated state with changing rheological properties leads to a major shift of their behavior in the microcirculation. Low levels of pseudopod formation or expression of adhesion molecules facilitate relatively free passage through microvessels while activated leukocytes with pseudopods and enhanced levels of adhesion membrane proteins become trapped in microvessels, attach to the endothelium and migrate into the tissue. The transformation of leukocytes into an activated state is seen in many diseases. While mechanisms for activation due to infections, tissue trauma, as well as non-physiological biochemical or biophysical exposures are well recognized, the mechanisms for activation in many diseases have not been conclusively liked to these traditional mechanisms and remain unknown. We summarize our recent evidence suggesting a major and surprising role of digestive enzymes in the small intestine as root causes for leukocyte activation and microvascular disturbances. During normal digestion of food digestive enzymes are compartmentalized in the lumen of the intestine by the mucosal epithelial barrier. When permeability of this barrier increases, these powerful degrading enzymes leak into the wall of the intestine and into the systemic circulation. Leakage of digestive enzymes occurs for example in physiological shock and multi-organ failure. Entry of digestive enzymes into the wall of the small intestine leads to degradation of the intestinal tissue in an autodigestion process. The digestive enzymes and tissue/food fragments generate not only activate leukocytes but also cause numerous cell dysfunctions. For example, proteolytic destruction of membrane receptors, plasma proteins and other biomolecules occurs. We conclude that escape of digestive enzymes from the intestinal track serves as a major source of cell dysfunction, morbidity and even mortality, including abnormal leukocyte activation seen in rheological studies.

Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction

“…However, it is clear that hydrolytic enzymes released by leukocytes, such as collagenase, elastase and matrix metalloproteinase-9, degrade important structural components of the endothelial glycocalyx, basement membrane, and ECM, thereby contributing to leukocyte-dependent microvascular barrier dysfunction in postischemic tissues (Altshuler, Kistler & Schmid-Schonbein, 2016; Carden & Korthuis, 1996; Granger & Korthuis, 1995; Kalogeris et al, 2012, 2016; Schmid-Schonbein, 2016). …”

“…For example, it is not clear what role protease-dependent receptor cleavage (Schmid-Schonbein, 2016; Mazor & Schmid-Schonbein, 2015) might play in postischemic EDD dysfunction. Moreover, interesting recent work has demonstrated that pentraxin 3, a soluble pattern recognition receptor that plays an important role in innate immune responses, induces EDD dysfunction via a P-selectin/MMP-dependent pathway that may feed into our hypothesized mechanism (Carrizzo, Lenzi, Procaccini, Damato, Biagioni, Ambrosio et al, 2015).…”