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UBC Theses and Dissertations

Intratracheal lipopolysaccharide exposure induced atherosclerotic plaque destabilization : a novel murine plaque vulnerability model Jaw, Jen Erh


Rationale: Literature has implicated lung inflammation as a risk factor for acute cardiovascular (CV) diseases (CVD), but the underlying mechanisms linking lung injury with CVD are largely unknown. Plasma neutrophilic myeloperoxidase (MPO) is an inflammatory biomarker for acute CVD, but its pathological role in CVD is unclear. Hypothesis: A murine model of atheromatous plaque vulnerability can be established by intratracheal Lipopolysaccharide (LPS) exposure. Neutrophils and MPO may contribute to this process. Approaches: LPS (3 mg/kg) or saline (control) was instilled directly into the lungs of male apolipoprotein E-knockout (ApoE-/-) C57BL/6J mice following 8 weeks of a Western-type diet. 24 hours later, atheromas in the right brachiocephalic trunk (BCT) were assessed for stability ex vivo using high-resolution optical projection tomography (OPT) and histology. Circulating neutrophils were depleted in vivo using neutrophil-specific antibodies to investigate the role of neutrophils in this model and determine the source of MPO. 4-aminobenzoic acid hydrazide (4-ABAH) was injected intraperitoneally to inhibit MPO. Results: LPS-exposed mice developed vulnerable plaques, characterized by intraplaque hemorrhage and thrombus compared to saline-exposed mice (p=0.0004). Plaque vulnerability was detectable as early as 8 hours post-intratracheal LPS instillation but not with intraperitoneal instillation. Depletion of circulating neutrophils attenuated plaque destabilization (P=0.027). MPO was found acutely localized in the vulnerable plaques and attached thrombi of LPS-exposed mice but not in the stable plaques of saline-exposed mice. Enzymatic inhibition of MPO in LPS-exposed mice decreased plaque vulnerability (P=0.038) and MPO/HOCl mediated oxidation (P=0.0076) Depletion of circulating neutrophils in LPS-exposed mice prevented intraplaque MPO accumulation, confirming that they were the major source of MPO in this model. Conclusion: We have established a novel plaque vulnerability model related to lung inflammation induced by intratracheal exposure to LPS. In this model, neutrophils play an important role in both lung inflammation and plaque destabilization. 3D OPT analysis revealed that during LPS-induced lung inflammation, MPO localizes acutely in atherosclerotic plaques and contributes to plaque vulnerability. MPO could be an important therapeutic target for prevention of acute CV events related to lung injury. This model could be useful for screening therapeutic targets to prevent acute vascular events related to lung inflammation.

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