The inflammatory response to arterial injury

Atherosclerosis as a disease is postulated to stem from a response to injury of the arterial wall by various stimuli. The inflammatory response is proposed to mediate intimal formation after injury. One pathway of cellular response to injury is through transcription factor NF-kB. We show that balloon injury of rat arteries leads to increased NF-kB activity and ICAM-1 expression, associated with increased medial cell proliferation early (3 days) and neointima formation (14 days) subsequently. Administration of high-dose aspirin, a known anti-inflammatory agent, reduced NF-kB activation, ICAM-1 expression, medial cell proliferation and neointimal formation. Studies on signal transduction that lead to activation of inflammatory genes have focused on the kinase-phosphatase balance mediating signaling pathways. Phosphorylation of specific residues of the transcription factors AP-1 and NF-kB is a critical step in their activation. Protein phosphatase 2A (PP2A) activity was reduced after injury, associated with AP-1 and NF-kB activation. Phosphatase activator octreotide inhibited the injury-induced PP2A inactivation associated with reduced AP-1 and NF-kB activity, and medial SMC proliferation. The effect of hypercholesterolemia on the inflammatory response to periadventitial cuff induced arterial injury was investigated in wild type and apoE deficient mice. Increased serum lipid levels resulted in increased arterial cholesterol content which augmented VCAM-1 expression. This resulted in increased presence of monocyte/macrophage in the wall of the injured artery and increased neointimal formation. Administration of a monoclonal VCAM-1 antibody reduced monocyte accumulation and intimal formation. Furthermore, antibody treatment partially reduced SMC migration in a model of in vitro injury. HDL has been shown to modulate the inflammatory response. Injured hypercholesterolemic apoE deficient mice fed cholesterol diet and treated with reconstituted HDL had reduced presence of MDA-modified LDL in the media after injury. There was also a reduction in VCAM-1 expression, monocyte/macrophage infiltration and reduced neointima formation. Various studies have indicated a complex role of the immune system in the response to injury and atherogenesis. Serum IFN-g was depressed after injury in chow-fed mice. Atherogenic diet also led to depressed serum IFN-g. Injury to immune-deficient RAG-1 KO mice resulted in robust neointimal formation. Reconstitution with T cells from atherogenic diet-fed mice had modest results but direct administration of rIFN-g inhibited neointimal formation. Reconstitution with B cells also inhibited neointimal formation. The systemic effect of arterial injury has not been scrutinized yet. It was hypothesized that injury would affect pre-existing plaques in other arteries of apoE KO mice. Carotid arterial injury had an anti-inflammatory effect on pre-existing plaques in aortic arch of apoE KO mice. This was characterized by less macrophage and lipid presence compared to controls. The injury also had a stabilizing effect on pre-existing plaques as indicated by more connective tissue stain. Plaque sizes were unchanged. The study affirms the inflammatory response to injury at various levels. In addition, new insights into the immune mechanism involved in arterial injury are also presented