The Role And Neuroimmune Mechanism Of Nerve Growth Factor (NGF) In The Pathogenesis Of Asthma

Asthma is a chronic inflammatory disorder of the airways in which many inflammatory cells, cytokines, chemokines and mediators play a role and asthma is characterized by airway broncho-obstruction and airway hyperresponsiveness. It is still not clear about the pathogenic mechanism of asthma. In addition to the theory " immuno-inflammation" , the theory " neurogenic inflammation" is arousing the interest of scholars more and more. However, little is known about the complex interactions of the nervous system with these inflammatory processes.Nerve growth factor (NGF) belongs to the neurotrophic family, which is related to the growth, development and survives of nerve cells. Recent researches show that NGF has more extensive biological activities, especially its roles in regulating the immune and inflammatory net are attracting the concern of man-y researchers. NGF is regarded as the ribbon between nervous system and immune system. The expression of NGF is increased remarkably in the lower respiratory tract and viscerosensory afferent sites of the asthmatic guinea pigs, and there are also overexpression of NGF in eosinophils, lymphocytes and alveoli macrophage in bronchoaveolar lavage fluid. Therefore the role and neuroimmune mechanism of nerve growth factor in trie pathogenesis of asthma is worth exploring.Calcitonin gene related peptide ( CGRP) is a polypeptide with 37 amino acids, which extensively exists in the central and peripheral nervous system. It has been demonstrated that CGRP has the function of constriction of bronchial smooth muscle, erudition of serum, secretion of mucus, which indicate that CGRP might be involved in the pathogenesis of asthma. The bodies of sensory neurons of lower respiratory tract are located at nodose ganglion and C7 ~ T5 spinal ganglion and the central axons terminate at spinal dorsal horn and solitary nucleus. The contents of CGRP in the trachea, bronchus, lungs, C7 ~T5 spinal ganglia and the correspondent spinal dorsal horn, nodose ganglia and solitarynucleus area in the asthmatic guinea pigs are upregulated significantly. Then, whether NGF is involved in the upregulation of CGRP during asthma is worth exploring.Tumor necrosis factor-a ( TNF-a ) and interleukin-1β (IL-1β ) are pro-inflammatory cytokines produced by activated mononuclear phagocytes and they have versatile biological activities. They play a fundamental role in the induction of multiple cellular and molecular interactions in the pathogenesis of asthma. Human lung fibroblasts may serve as a source of NGF in the lung, positively regulated by TNF-a and IL-1β. Then, whether TNF-a and IL-1β can regulate the expression of NGF and what the effect of NGF on TNF-a and IL-1β is in asthmatic guinea pigs are worth exploring.Tyrosine kinase A (TrkA) is the NGF high-affinity receptor. It is highly important to trigger NGF and respond to the biological functions of NGF. When NGF binds to TrkA, the tyrosine kinase signal transduction system will be activated, and NGF will show a great diversity of biological functions. But whether TrkA can mediate the involvement of NGF in the pathogenesis of asthma still remains poorly understood.MethodsAsthmatic model was prepared by using Ovalbumin. Radioimmunoassay was used to determine the alteration of CGRP levels in the lower respiratory tract and visceral afferent sites while NGF was absent (inhalation of NGF antibody through nasal cavity) in the asthmatic guinea pigs. By means of in situ hybridization to investigate the changes of TNF-a mRNA expression and the inhibitory effect of the antibody against NGF in lower respiratory tract and viscerosensory afferent system of experimental asthmatic guinea pigs. By means of immunohis-tochemistry to investigate the changes of IL-1β immunoreactivity and the regulatory effect of NGF in lower respiratory tract and viscerosensory afferent sites of the asthmatic guinea pigs. By means of immunohistochemistry to investigate the changes of the NGF high-affinity receptor TrkA immunoreactivity and the inhibitory effect of the an...