Mechanisms for cell activation and its consequences for biorheology and microcirculation: Multi‐organ failure in shock

Article type: Research Article

Authors: Schmid‐Schönbein, Geert W.^; | Kistler, Erik B. | Hugli, Tony E.

Affiliations: Department of Bioengineering, Whitaker Institute for Biomedical Engineering, University of California, San Diego, La Jolla, CA, USA | La Jolla Institute for Molecular Medicine, La Jolla, CA, USA

Note: [] Address for correspondence: Dr. Geert W. Schmid‐Schönbein, Department of Bioengineering, Whitaker Institute for Biomedical Engineering, University of California, San Diego, La Jolla, CA, 92093‐0412, USA. Tel.: +1 858 534 3852; Fax: +1 858 534 6896; E‐mail: [email protected].

Abstract: Activation of cells in the vascular compartment causes profound alteration of cell rheological properties with impairment of the microcirculation and initiation of inflammatory reactions. Many cardiovascular diseases have been shown to be associated with cell activation and inflammation. While this situation offers the opportunity for new interventions against the deleterious effects of cell activation, there is the need for a better understanding of the mechanisms that lead to cell activation in the first place. We review here several mechanisms for cell activation in the circulation. We show that in shock, a condition associated with severe forms of cell activation, humoral cell activation factors can be detected in plasma. Further analysis indicates that the source of these humoral activators may be due to the action of pancreatic digestive enzymes in the intestine. Ischemia may serve to open the intestinal brush border and permit entry of pancreatic enzymes into the wall of the intestine to initiate self digestion. In this process low molecular weight but potent cell activators are produced which may escape via the intestinal circulation and the lymphatics into the general circulation. Inhibition of pancreatic enzymes in the lumen of the intestine leads to complete attenuation of humoral activator production as well as many of the deleterious sequelae that accompany shock, such as inflammation and multi‐organ failure. We outline a method to carry out biochemical isolation of the cell activators derived from pancreatic enzymes. This analysis shows that there are multiple species of cell activators above and beyond currently known species, many of which have molecular weights below 3000 Da. Identification of the mechanisms that lead to cell activation is an important part to understand the mechanisms that lead to alterations of rheological properties of blood cells in disease and dysfunction of the endothelium and parenchymal cells. Our current evidence suggests that pancreatic digestive enzymes and tissue enzymes may play a central role in humoral activator production.

Keywords: Endothelium, leukocytes, actin polymerization, adhesion molecules, pancreatic enzymes, proteases, inflammatory mediators, shock, ischemia, reperfusion, intestine, brush border, extracellular proteins, SepPak elution, platelet activating factor, leukotriene, peptides

Journal: Biorheology, vol. 38, no. 2-3, pp. 185-201, 2001