Background-With consideration of the central role of the innate immune system in atherogenesis and mannose-binding lectin (MBL) as an innate regulator of immunity, the role of MBL in experimental and human atherosclerosis was assessed. Methods and Results-With the use of immunohistochemistry and polymerase chain reaction, deposition and gene expression of MBL-A and -C were assessed in murine atherosclerosis from mice deficient for the low-density lipoprotein receptor (LDLR Ϫ/Ϫ ) after 10 or 18 weeks of high-fat feeding. MBL was present and was produced in 10-week-old lesions, whereas deposition and gene expression were minimal after 18 weeks of high-fat feeding and absent in healthy vasculature. Interestingly, deposition of MBL-A and -C differed: MBL-A predominantly localized in upper medial layers, whereas MBL-C was found in and around intimal macrophages. To further study the role of local MBL production by monocytic cells in atherosclerosis, LDLR Ϫ/Ϫ mice with MBL-A and -C Ϫ/Ϫ monocytic cells were construed by bone marrow transplantation. Mice carrying MBL-A and -C double deficient macrophages had increased (30%) atherosclerotic lesions compared with wild-type controls (Pϭ0.015) after 10 weeks of high-fat diet. Subsequently, analysis of MBL deposition and gene expression in advanced human atherosclerotic lesions revealed the presence of MBL protein in ruptured but not stable atherosclerotic lesions. Putatively in agreement with murine data, no MBL gene expression could be detected in advanced human atherosclerotic lesions. Conclusions-These Clinical Perspective p 2195Mannose-binding lectin (MBL) is a C-type or Ca 2ϩ -dependent lectin that can act as an opsonin and can activate complement through its own and evolutionary conserved lectin pathway. 5 There is considerable variation in activating properties and plasma levels between individuals. These variations are caused by 3 first exon mutations (at codons 52, 54, and 57) and polymorphisms in the promoter region (at positions Ϫ550 [H/L] and Ϫ221 [X/Y]) of the structural gene (mbl2). 6 Studies on the development of vascular diseases, including atherosclerosis in MBL-sufficient and -insufficient human subjects, suggested that the MBL C-type lectin influences vascular disease. 7-13 Frequently, low MBL levels in MBL-deficient patients have been associated with an earlier disease onset or a more progressive disease course compared with their MBL-sufficient counterparts. However, opposing contributions by MBL to atherogenesis have been proposed as well. MBL-mediated modulation of Chlamydia pneumoniae infection, differences in complement activation, deficiencies in MBL-opsonizing capacities, and unknown sex- The long-existing tenet that merely centrally produced complement components drive inflammatory reactions has recently been challenged. 16 -19 Locally synthesized complement proteins such as C1q and C3 greatly determine the innate immune response, contributing to, for example, ischemia/reperfusion-induced tissue damage. 19 First reports suggest similar effects...
BackgroundRecently, we observed that small-intestinal ischemia and reperfusion was found to entail a rapid loss of apoptotic and necrotic cells. This study was conducted to investigate whether the observed shedding of ischemically damaged epithelial cells affects IR induced inflammation in the human small gut.Methods and FindingsUsing a newly developed IR model of the human small intestine, the inflammatory response was studied on cellular, protein and mRNA level. Thirty patients were consecutively included. Part of the jejunum was subjected to 30 minutes of ischemia and variable reperfusion periods (mean reperfusion time 120 (±11) minutes). Ethical approval and informed consent were obtained. Increased plasma intestinal fatty acid binding protein (I-FABP) levels indicated loss in epithelial cell integrity in response to ischemia and reperfusion (p<0.001 vs healthy). HIF-1α gene expression doubled (p = 0.02) and C3 gene expression increased 4-fold (p = 0.01) over the course of IR. Gut barrier failure, assessed as LPS concentration in small bowel venous effluent blood, was not observed (p = 0.18). Additionally, mRNA expression of HO-1, IL-6, IL-8 did not alter. No increased expression of endothelial adhesion molecules, TNFα release, increased numbers of inflammatory cells (p = 0.71) or complement activation, assessed as activated C3 (p = 0.14), were detected in the reperfused tissue.ConclusionsIn the human small intestine, thirty minutes of ischemia followed by up to 4 hours of reperfusion, does not seem to lead to an explicit inflammatory response. This may be explained by a unique mechanism of shedding of damaged enterocytes, reported for the first time by our group.
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