TNF is one of the most frequently studied pleiotropic cytokine of the TNF family. TNF plays an important role as a cytokine in the essential immune response. The production of TNF is primarily done by macrophages due to the stimulation of membrane-bound pattern-recognition molecules. However, it is also synthesised by a few other proinflammatory cells such as dendritic cells, monocytes, B cells, CD4+ cells, neutrophils, eosinophils, mast cells, and the structural cells. TNF is initially produced as a membrane-anchored protein with properties that causes it to be biologically active. It then undergoes the process of cleaving by TNF converting enzymes to release the free protein. These proteins then form homotrimers which are biologically active and act on ubiquitously expressed TNF receptors 1 and 2. (Nie 2011) Through recent studies, TNF has been involved in the pathophysiologic mechanisms of several inflammatory diseases. The likelihood that TNF contributes to the inflammatory response as seen in the asthmatic airway is consolidated by the fact that TNF mRNA and levels of protein were increased in the airways of asthmatic patients. (Choi 2005) More importantly, the administration of inhaled recombinant TNF to normal subjects have been shown to lead to the development of airway hyperresponsiveness and airway neutrophilia. Some studies have suggested that airway hyperresponsiveness could be caused by the effect of TNF acting directly onto the smooth muscles of the airway. (Brightling 2008) In human airway smooth muscles that has been cultured, that has been able to retain their physiological responsiveness and express both the TNF receptors, TNF then has the ability to modify the proinflammatory gene expressions that may take on an important role in the pathogenesis of allergic asthma. (Tilba 2003) Besides that, TNF has a few other variations of actions that might show great significance to asthma. TNF is a chemoattractant for eosinophils and neutrophils. Besides that, it also increases the effect of cytotoxicity of eosinophils on the endothelial cells and is implicated in the activation of T cells. Moreover, TNF increases the epithelial expression of adhesion molecules. Furthermore, the upregulation of adhesion molecules may have the possibility of stimulating the migration of inflammatory cells to the lungs and hence have an indirect effect to the development of airway hyperresponsiveness. (Brightling 2008). However, the exact role that TNF plays in the process of pathogenesis of asthma still remains to be unclear and further research has to be carried out in order for it to be explained.
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In this article from BJP, Makwana et al has made comparisons between the contractions of the isolated trachea of guinea pigs incubated with saline or TNF for 1, 2 or 4 days to EFS, 5-HT or MCh. Based on the in vitro studies, the contractions of both the tracheal segments that were treated and untreated with TNF were displayed to suggest that the EFS-evoked contractions were of an indirect process. Furthermore, the ACh released from the innervating post-ganglionic neurons that caused the activation of the muscarinic receptors which are located on the smooth muscle help mediates the process. Similar to fresh tissues, the contractions of segments of trachea that were exposed to TNF was also indirect when evoked by 5-HT. It was suggested that the contractions were mediated by the stimulation of the muscarinic receptors by the ACh which was released from the tracheal epithelium in response to 5-HT activating the 5-HT2A receptor. Besides that, the direct stimulation of the smooth muscle through the stimulation of M3 muscarinic receptors help facilitate the contractions of the tracheal segments that were treated with TNF and untreated in response to MCh. The results obtained from the experiment showed that the isolated tracheal segments of the guinea pig cultured with TNF for 1, 2 or 4 days resulted in an increase in contractility in response to EFS and 5-HT, but not MCh. (Makwana et al 2012) Based on the in vivo studies, the bronchoconstriction in the guinea pigs 6 hours after intratracheal instillation of saline or TNF was compared to vagal nerve stimulation. The instillation of TNF increased the bronchoconstrictorâ€™s response to EFS and 5-HT significantly, but not to MCh. This therefore supports the results obtained from the in vitro studies. The mechanism of how the bronchoconstrictor responded to the EFS and 5-HT were indirectly facilitated by ACh acting on the smooth muscles of the airway which showed some similarities to MCh due to their antagonism by atropine. Moreover, the reason for contractions due to 5-HT but not the EFS or MCh was because of antagonism by ketanserin. From previous studies, it was observed that incubations of short periods of guinea pig isolated trachea with TNF can bring upon the development of a hypercontractile phenotype of the airway smooth muscle due to bronchoconstrictors that mainly act on the smooth muscle. (Pennings et al., 1998)
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Given that the present experiments were carried out in both in vitro and in vivo, studies such as these are required to be done on human patients in order to confirm the effect of TNF in the human body. Nevertheless, the study by Makwana et al. strongly supports that the exposure to TNF regulates the phenotype of the airways by selectively increasing the neuronal and epithelium derived release of ACh with changing the action of contraction on the muscle. With the results obtained from this study, the mechanisms involved in asthma are better understood although more research is still required. However, this study carried out has widened the scope of research to be able to carried out.