The Efficacy Of Immunotherapy On Atherogenesis And Sepsis

Atherosclerosis is a progressive inflammatory disease characterized by the accumulation of lipids and fibrous elements in arteries. It is the one of the major cardiovascular diseases. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations, cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia. The lesions of atherosclerosis occur principally in large and medium-sized arteries and they may be present throughout a person’s lifetime. Fibrous cap, which is the earliest type of lesion, seems common in infants. Epidemiological studies have revealed numerous risk factors for atherosclerosis. They can be grouped into factors with an important genetic component (such as familial hypercholesterolemia, hypertension, etc) and those that are largely environmental (such as high-fat diet, alcohol, smoke, lack of exercise, etc). Nowadays, effective drugs for lowering cholesterol and high blood pressure have been developed. In particular, the statins lower levels of atherogenic lipoproteins and dramatically decrease clinical events and mortality from atherosclerosis.Fibrinolytic system is implicated in numerous biological functions which are important for the development of atherosclerosis, such as fibrin and extracellular matrix (ECM) degradation, cytokines metabolism, cell migration and inflammation. Urokinase-type plasminogen activator (uPA) and its cellular receptor, uPAR are the main activators for fibrinolytic system. Abundant data suggests that uPA and uPAR may play a pivotal role in the initiation and progression of atherosclerosis. Clinical investigations show that both uPA and uPAR are up-regulated in atherosclerotic lesions compared with the normal artery. However, the exact role of uPA in atherosclerosis is still not known because of the conflicting data from different atherosclerotic models. UPA and uPAR are also up-regulated in the lesions of atherosclerotic model. Macrophage-targeted over-expression of uPA increases atherosclerotic lesions in ApoE-/- mice. However, deletion of plasminogen (plg), one of the major members of fibrinolytic system, increases the progression of AS while macrophage targeted over-expression of collagenase had the contradictory effect. These studies predicted both pro- and anti-atherogenic role of uPA. According the previous studies, we hypothesize here that the pro-atherogenic role of uPA might be induced through binding to uPAR and the subsequent activation of signal transduction, while the protease activity of uPA (B chain) is anti-atherogenic through the degradation of ECM to reduce the binding site for inflammatory cells and proteins. In the present study, we evaluated the effect of recombinant human amino terminal fragment of uPA (rhATF) on atherogenesis, using balloon injury atherosclerotic model. Aspirin significantly reduced the lesion area to 29.7% compared with the control group (48.19%, p=0.012). The lesion area was also down-regulated in the berberine group (37.0%), although no significant difference was found (p=0.16). These results were accord with the previous studies and it also demonstrated that our model worked. We found rhATF vaccination significantly reduced the atherosclerotic lesion area (p< 0.01) as well as plasma level of total cholesterol (TC) and low density lipoprotein (LDL) (p<0.05). As down-regulation of plasma lipid level is the most efficient therapy for atherosclerosis now, present study unveiled a probable anti-atherosclerosis role for rhATF vaccination through down-regulating the levels of cholesterol and LDL by blocking the binding between uPA and uPAR.Sepsis is a systemic inflammatory disease caused by infection. It is one of the major causes of death in intensity care unit (ICU). Despite a long history of this disease, and more than 20 years of extensive research and development of numerous therapeutic approaches used in clinical settings, sepsis is still life-threatening, with a poor outcome. Depending on the standards of medical care, the worldwide mortality rate in septic humans ranges from 30% to 70%(with an average mortality rate of-50%). Currently, available therapies for sepsis are still limited to several simple clinical interventions.There is now evidence that sepsis is a condition that affects not only the immune system but also other biological systems, such as the coagulation system, compliment system and the autonomic nervous system (ANS). Innate immunity is the first defense line and sepsis always starts when the initiate response is not appropriate. As one of the most important phagocytes in innate immunity, macrophage plays a pivotal role in sepsis. A lot of pathogen recognition receptors (PRRs) such as scavenger receptors (SRs) and toll-like receptors (TLRs) are expressed on the cell surface of macrophages. The binding between PRRs and pathogen associated molecular patterns (PAMPs) of microbe accounts for the rapid kinetics of innate immune responses. Macrophage is also the main source of cytokines and is important for the initiation of inflammation. High sensitivity to the lethal effects of lipopolysaccharide (LPS) is achieved in LPS resistant C3H/HeJ mice after transferring of LPS activated C3H/HeN macrophages.In the present study, we prepared the rabbit polyclonal antibody against activated macrophages (Ab-mph) and examined its effect on septic model and RAW264.7 cells. Data revealed that pre-treatment with Ab-mph significantly down-regulated the level of TNF-α and IL-6 in plasma and ascites (p<0.05). It also inhibited the migration of inflammatory cells (p< 0.01) as well as the growth of plasma bacteria (p<0.05). Meanwhile, the survival rate of sepsis which was induced by intraperitoneal inoculation of cecal bacteria was up-regulated in a dose-dependent way (p<0.01). In vitro studies indicated that pretreatment with Ab-mph significantly inhibited the secretion of IL-6 after LPS stimulation.