Selective and marked decrease of complement receptor C5aR2 in human thoracic aortic aneurysms: a dysregulation with potential inflammatory effects.

Objective: The aetiology of thoracic aortic aneurysm (TAA) is largely unknown, but inflammation is likely to play a central role in the pathogenesis. In this present study, we aim to investigate the complement receptors in TAA. Methods: Aortic tissue and blood from 31 patients with non-syndromic TAA undergoing thoracic aortic repair surgery were collected. Aortic tissue and blood from 36 patients with atherosclerosis undergoing coronary artery bypass surgery or aortic valve replacement were collected and served as control material. The expression of the complement anaphylatoxin receptors C3aR1, C5aR1 and C5aR2 in aortic tissue were examined by quantitative RT-PCR and C5aR2 protein by immunohistochemistry. Colocalisation of C5aR2 to different cell types was analysed by immunofluorescence. Complement activation products C3bc and sC5b-9 were measured in plasma. Results: Compared with controls, TAA patients had substantial (73%) downregulated gene expression of C5aR2 as seen both at the mRNA (p=0.005) level and protein (p=0.03) level. In contrast, there were no differences in the expression of C3aR1 and C5aR1 between the two groups. Immunofluorescence examination showed that C5aR2 was colocalised to macrophages and T cells in the aortic media. There were no differences in the degree of systemic complement activation between the two groups. Conclusion: Our findings suggest downregulation of the C5aR2, regarded to act mainly anti-inflammatory, in electively operated TAA as compared with non-aneurysmatic aortas of patients with aortic stenosis and/or coronary artery disease. This may tip the balance towards a relative increase in the inflammatory responses induced by C5aR1 and thus enhance the inflammatory processes in TAA.

Reduced immune responses to an aseptic inflammation in mice with congestive heart failure.

We previously found that mice with congestive heart failure (CHF) were anemic, had decreased bone marrow haematopoiesis and functionally impaired neutrophilic granulocytes despite normal blood concentrations of these cells. We now asked if CHF-mice could mount an adequate immune response when challenged with an acute inflammation. A postinfarction heart failure was induced in mice. Six weeks later the mice had developed CHF. At that time a sterile peritonitis was induced by injection of a casein digest. Five hours after this injection a marked neutrophilia had developed. Specimens were then obtained from peritoneal washings, bone marrow and blood. Total bone marrow cell numbers were halved in CHF-peritonitis mice compared with sham-peritonitis mice. Bone marrow colony-forming cell numbers in CHF-peritonitis mice were only 14% of those in sham-peritonitis mice. The mobilization of leucocytes to the blood was much lower in CHF-peritonitis mice than in sham-peritonitis mice (5.6 vs. 8.1 million cells/mL), as was the peritoneal influx of these cells (1.6 vs. 4.1 million cells). A profound decline (>50%) in the functional activity, determined with various in vitro assays, was evident for both neutrophilic granulocytes and lymphocytes from CHF-peritonitis mice. Heart failure after myocardial infarction in mice may severely compromise their ability to combat an inflammatory challenge.