title: Lysozyme, a mediator of sepsis that deposits in the systemic vasculature and kidney as a possible mechanism of acute organ dysfunction.
abstract: In septic shock (SS), dysfunction of many organ systems develops during the course of the illness, although the mechanisms are not clear. In earlier studies, we reported that lysozyme-c (Lzm-S), a protein that is released from leukocytes and macrophages, was a mediator of the myocardial depression and vasodilation that develop in a canine model of Pseudomonas aeruginosa SS. Whereas both of these effects of Lzm-S are dependent on its ability to intrinsically generate hydrogen peroxide, we subsequently showed that Lzm-S can also deposit within the vascular smooth muscle layer of the systemic arteries in this model. In the present study, we extend our previous findings. We used a canine carotid artery organ bath preparation to study the time course and dose dependence of Lzm-S deposition within the vascular smooth muscle layer. We used a human aortic vascular smooth muscle cell preparation to determine whether Lzm-S can persistently inhibit contraction in this preparation. We also used a canine P. aeruginosa model to determine whether Lzm-S deposition might occur in other organs such as the kidney, liver, and small intestine. The results showed that, in the carotid artery organ bath preparation, Lzm-S deposition occurred within minutes of instillation and there was a dose-response effect. In the human aortic vascular smooth muscle cell preparation, Lzm-S inhibited contraction during a 4-day period. In the in vivo model, Lzm-S accumulated in the kidney and the superior mesenteric artery. In a canine renal epithelial preparation, we further showed that Lzm-S can be taken up by the renal tubules to activate inflammatory pathways. We conclude that Lzm-S can deposit in the systemic vasculature and kidneys in SS, where this deposition could lead to acute organ dysfunction.
authors.affiliation: *Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico; and Departments of †Pharmacology and Therapeutics, ‡Medicine, and §Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Jose
authors.initials: J
authors.lastname: Gotes
authors.forename: Krika
authors.initials: K
authors.lastname: Kasian
authors.forename: Hans
authors.initials: H
authors.lastname: Jacobs
authors.forename: Zhao-Qin
authors.initials: ZQ
authors.lastname: Cheng
authors.forename: Steven N
authors.initials: SN
authors.lastname: Mink
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology / Q000473:pathology; D007686:Kidney Tubules, Distal / Q000201:enzymology* / Q000473:pathology; D008264:Macrophages / Q000201:enzymology*; D008638:Mesenteric Arteries / Q000201:enzymology / Q000473:pathology; D009113:Muramidase / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D009924:Organ Culture Techniques; D011552:Pseudomonas Infections / Q000201:enzymology / Q000473:pathology; D011550:Pseudomonas aeruginosa; D018805:Sepsis / Q000201:enzymology* / Q000473:pathology
chemical_list: D009113:Muramidase