Recurrent perivascular inflammation induced by lipopolysaccharide (endotoxin) results in the formation of atheromatous lesions in vivo

Abstract

Bacteria and viruses are suspected to induce arteriosclerosis; however, most investigators have focused on coincidences rather than causal relationships. The aim of this work was to establish a rabbit model in which the vessel reaction to local perivascular injection of defined bacterial products can be analyzed. A total of 23 rabbits were randomized to four groups. Groups A and B were fed a normal diet, groups C and D were fed a cholesterolenriched diet. Groups A and C were treated with a single perivascular injection of bacterial lipopolysaccharide (LPS, endotoxin) placed next to auricular, carotid and femoral arteries, and sodium chloride placed next to the contralateral arteries (control). Group B and D animals were treated with repeated perivascular injections over 90 days. Vascular tissues (n ¼ 116 treated segments of 23 rabbits) were analyzed using morphometry at histology, and using immunohistochemistry to detect macrophages, lymphocytes and vascular smooth muscle cells. LPS treatment resulted in transient focal intima thickening. After single LPS application, no increase in atheromatous lesion formation was observed in comparison with controls (group C, lesion area index 0.03170.012 vs 0.01570.006, P ¼ 1.0). Repeated LPS application resulted in significant atheromatous lesion formation compared with saline control (group D, lesion area index 0.14870.049 vs 0.00870.006, P ¼ 0.003) in hypercholesterolemic rabbits. Repeated LPS inflammation in normocholesterolemic did not lead to atheromatous lesion formation (intima media ratio 0.0470.01 vs 0.0470.007, P ¼ 1.0). Single perivascular administration of low-dose bacterial LPS resulted in transient focal intimal thickening, while significant increase in lesion formation occurred after repeated LPS application in cholesterol-fed animals. In conclusion, this animal model will allow the assessment of the impact of defined dosages of different bacterial pathogens onto the vascular wall in the context of atherogenesis. The atheromatous lesion-promoting effect of repeated perivascular administration of LPS supports the hypothesis that bacterial pathogens may be involved in atherogenesis.

Arginase I Attenuates Inflammatory Cytokine Secretion Induced by Lipopolysaccharide in Vascular Smooth Muscle Cells

“…Some proinflammatory factors, such as lipopolysaccharide (LPS), trigger the inflammation response and promote the generation of inflammatory cytokines by VSMCs 1 and are demonstrated to be involved in atherogenesis. 2 Increased inflammatory cytokine activity promotes infiltration of inflammatory cells and then augments the inflammatory response. 3 VSMCs in the medial wall of blood vessels are normally quiescent and express a differentiated phenotype to generate and maintain vascular tone.…”

Chronic perivascular inoculation with Chlamydophila pneumoniae results in plaque formation in vivo

“…43 Transient migration of VSMCs into neointima resulting from perivascular inflammation using LPS from E. coli in normocholesterolemic rabbits has been described previously by our group. 19 Further studies on lesion initiation during the early phase of the inflammatory injury are needed as we did not observe significant presence of inflammatory cells after 16 weeks of repeated infections using CPN either in its viable or in inactivated form. Moreover, the local inoculation of fractionated bacterial components will allow identification of atherogenic factors.…”

“…Intima media ratio was calculated from the measured area of intima and area of media, and lesion area index from the lesion area related to the area of media, as published previously. 19 To prevent bias from an operator-dependent effect, morphometric analyses were performed independently of the operator (MGE) by CVR who was blinded towards the perivascular treatment performed.…”

A Rabbit Model of Spontaneous Thrombosis Induced by Lipopolysaccharide

“…Several studies have reported that repeated injections of endotoxin in animals significantly accelerates atherosclerosis, suggesting that LPS-induced immune mechanisms play an important role in the atherosclerotic process 5,23,24) . The findings of the present study are consistent with those of the above studies, although they are in direct contrast with the results of earlier studies in which no proatherogenic effects of endotoxin administration were observed in piglets or rabbits fed a high-cholesterol diet 25,26) .…”