Application Of Immunomodulatory Agents Against Atherosclerosis And Pulmonary Fibrosis In Mouse

Atherosclerosis is the major cause of cardiovascular disease, which increasingly threatens human health worldwide. Depending on lipids lowing effects, statins dramatically decrease clinical events and mortality caused by atherosclerosis. However, heart disease and stroke remain by far the most common causes of death. Thus there is a growing quest for novel drugs in clinical therapy. Inflammatory process plays a major role during different steps, from an early stable atherosclerotic plaque to an advanced plaque prone to rupture. As abnormal immune responses act as an important driving factor, application of immunomodulatory agents offers the possibility of new pharmacological interventions in atherosclerosis.Toll like receptors (TLRs) are a family of pattern-recognition receptors of innate immunity that initiate inflammatory pathways, and their importance in atherosclerosis pathogenesis, especially TLR2, has been well established. In this study, we firstly demonstrated that treatment with anti-TLR2 antibody resulted in reduction and stabilization of advanced atherosclerotic lesions by decreasing the plaque size and necrotic cores, higher expression of collagen andα-SMA in lesions in the brachiocephalic artery of Apoe-/- mice. With the equal effect of TLR2 deficiency, treatment with anti-TLR2 antibody inhibited the accumulation of macrophage in plaques, the expression of inflammatory mediators in the aortas, including MMP-2, TNF-αand IL-6, and the activation of transcription factor NF-κB. ER-stressed macrophage apoptosis in advanced lesions were also dramatically inhibited in the treatment groups, partially depending on regulation of CHOP expression. In summary, the results of this study, compared with recent findings in TLR2-deficient mouse model of atherosclerosis, indicate that anti-TLR2 antibody treatment could act as an effective therapeutic method to protect from advanced atherosclerosis. While TLR2 expressed on endothelial cells is required for disease initiation, in advanced atherosclerotic lesions in which macrophages undergoing apoptosis TLR2 on macrophage surfaces may mediate or amplify the apoptosis signal. So antibodies or antagonists of TLR2 should be developed as a key therapeutic drug in future. CFX is the fermentative polysaccharides of medical mushroom with potent immunomodulatory activity. We found that CFX treatment markedly inhibited the formation of atherosclerosis in the whole aortas, the aortic root and the brachiocephalic arteries of Apoe mice on atherogenic diets. And in Apoe-/-mice with established atherosclerosis, administration of CFX significantly improved advanced atherosclerotic lesions, which were related to suppression of inflammatory responses.Although the detailed mechanisms are still not well understood, inflammatory responses also contribute to the pathogenesis of pulmonary fibrosis, a disease characterized by excessive matrix deposition and destruction of the normal lung architecture. Using the mouse model of bleomycin-induced pulmonary fibrosis, our preliminary findings demonstrated the protective effects of TLR5 agonist on inflammation and fibrosis. These findings will contribute to identifying the new molecular targets of pulmonary fibrosis, and providing research clues for the development of new drugs.