Anti-MSR1 monoclonal antibody, clone FQS8647

Macrophages are distributed in all peripheral tissues and play a critical role in the first line of the innate immune defenses against bacterial infection by phagocytosis of bacterial pathogens through the macrophage scavenger receptor 1 (MSR1). Within tissues, the partial pressure of oxygen (pO(2)) decreases depending on the distance of cells from the closest O-2-supplying blood vessel. However, it is not clear how the expression of MSR1 in macrophages is regulated by low pO(2). On the other hand, hypoxia-inducible factor (HIF)-1 alpha is well known to control hypoxic responses through regulation of hypoxia-inducible genes. Therefore, we investigated the effects of hypoxia and HIF-1 alpha on MSR1 expression and function in the macrophage cell line RAW264. Exposure to 1% O-2 or treatment with the hypoxia-mimetic agent cobalt chloride (CoCl2) significantly suppressed the expression of MSR1 mRNA, accompanied by a markedly increase in levels of nuclear HIF-1 alpha protein. The overexpression of HIF-1 alpha in RAW264 cells suppressed the expression of MSR1 mRNA and protein, transcriptional activity of the MSR1 gene, and phagocytic capacity against the Gram-positive bacteria Listeria monocytogenes. The suppression of MSR1 mRNA by hypoxia or CoCl2 was inhibited by YC-1, an inhibitor of HIF-1 alpha, or by the depletion of HIF-1 alpha expression by small interference RNA. These results indicate that hypoxia transcriptionally suppresses MSR1 expression through HIF-1 alpha.

Objective: The aim of the study was to detect inter-relations between the mechanical conditions and material properties of abdominal aortic aneurysm (AAA) wall and the underlying local gene expression of destabilizing inflammatory, proteolytic, and structural factors. Methods: During open surgery, 51 tissue samples from 31 AAA patients were harvested. Gene expression of collagen types I and III, inflammatory factors CD45 and MSR1, proteolytic enzymes matrix metalloproteinases 2 and 9, and tissue inhibitor of matrix metalloproteinase 1 was analyzed by reverse transcription-polymerase chain reaction. Material properties of corresponding AAA tissue samples were assessed by cyclic sinusoidal and destructive testing. Local mechanical conditions of stress and strain were determined by advanced nonlinear finite element analysis based on patientspecific three-dimensional AAA models derived from preoperative computed tomography data. Results: In the AAA wall, all parameters analyzed were significantly expressed at the messenger RNA level. With respect to mechanical properties of the aneurysmatic wall, expression of collagen III correlated with the stiffness parameter a (r = -0.348; P = .017), and matrix metalloprotease 2 correlated with the stiffness parameter beta and wall strength (r = -0.438 and -0.593; P = .005 and P < .001). Furthermore, significant relationships were observed between local AAA diameter and the expression of CD45, MSR1, and tissue inhibitor of matrix metalloproteinase alpha (r = 0.285, 0.551, 0.328; P < .05). However, we found no inter-relation of local calculated wall stresses and strains with gene expression. Conclusions: Our results show for the first time that gene expressions of destabilizing factors within AAA tissue might be correlated to geometric and mechanical properties of the AAA wall. However, we found no influence of local mechanical conditions on gene expression of these factors. Therefore, these preliminary results are still ambiguous.