Rabbit Anti-Human MCP-3 monoclonal antibody, clone 4I2M4

Pulmonary inflammation and increased production of the inflammatory cytokine IL-1 beta are associated with the development of bronchopulmonary dysplasia (BPD) in premature infants. To study the actions of IL-1 beta in the fetal and newborn lung in vivo, we developed a bitransgenic mouse in which IL-1 beta is expressed under conditional control in airway epithelial cells. Perinatal pulmonary expression of IL-1 beta caused respiratory insufficiency that was associated with increased postnatal mortality. While intrauterine growth of IL-1 beta expressing mice was normal, their postnatal growth was impaired. IL-1 beta disrupted alveolar septation and caused abnormalities in alpha-smooth muscle actin and elastin deposition in the septa of distal airspaces. IL-1 beta disturbed capillary development and inhibited the production of vascular endothelial growth factor in the lungs of infant mice. IL-1 beta induced the expression of CXC chemokines KC (CXCL1) and macrophage inflammatory protein-2 (CXCL2) and of CC chemokines monocyte chemotactic protein (MCP)-1 (CCL2) and MCP-3 (CCL7), consistent with neutrophilic and monocytic infiltration of the lungs. IL-1 beta caused goblet cell metaplasia and bronchial smooth muscle hyperplasia. Perinatal expression of IL-1 beta in epithelial cells of the lung caused a lung disease that was clinically and histologically similar to BPD.

Infiltration of macrophages into the artery wall plays detrimental roles during hypertension by promoting vascular inflammation and endothelial dysfunction, and it occurs via a chemo-attractant action of chemokines on macrophage cytokine receptors. We sought to identify the key chemokine receptors associated with macrophage infiltration into the vascular wall during deoxycorticosterone acetate (DOCA)/salt-induced hypertension in mice and to evaluate the impact of pharmacological inhibition of these receptors on blood pressure and leukocyte accumulation. Mice treated with DOCA/salt for 21 days displayed markedly elevated systolic blood pressure (158 +/- 2 versus 114 +/- 5 mm Hg in sham group; P<0.0001). Polymerase chain reaction screening via a gene array of 20 chemokine receptors indicated an increased expression of CCR2 in aortas of DOCA/salt-treated mice. Real-time polymerase chain reaction confirmed mRNA upregulation of CCR2 in aortas from DOCA/salt-treated animals and of the CCR2 ligands CCL2, CCL7, CCL8, and CCL12 (all >2-fold versus sham; P<0.05). Flow cytometry revealed 2.9-fold higher macrophage numbers (ie, CD45(+) CD11b(+) F4/80(+) cells) in the aortic wall of DOCA/salt versus sham-treated mice. Intervention with a CCR2 antagonist, INCB3344 (30 mg/kg per day, IP), 10 days after the induction of hypertension with DOCA/salt treatment, reduced the aortic expression of CCR2 mRNA and completely reversed the DOCA/salt-induced influx of macrophages. Importantly, INCB3344 substantially reduced the elevated blood pressure in DOCA/salt-treated mice. Hence, our findings highlight CCR2 as a promising therapeutic target to reduce both macrophage accumulation in the vascular wall and blood pressure in hypertension. (Hypertension. 2012;60:1207-1212.). Online Data Supplement