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Abstract

A number of studies have implicated severe infections early in life as a risk factor for the subsequent development of asthma. In particular it has been suggested that respiratory syncytial virus (RSV) infection may enhance the development of "allergic" inflammatory responses when the host is exposed to allergens after an episode of bronchiolitis. It has also been suggested that neuronal mechanisms are important in RSV infection and subsequent airway hyperreactivity. Recently we advanced the hypothesis that immune and neuronal mechanisms may be linked and that combined neuroimmune responses may be in play. In the airways a dense network of sensory nerve fibers is strategically placed just below the epithelial surface so that any change in the bronchial environment may stimulate the release of the proinflammatory neuropeptide substance P. During RSV infection, stimulation of these nerves causes a marked increase in airway vascular permeability over that in pathogen-free rats and results in an increase in overall inflammatory status. Our work has revealed that these changes are mediated by the high affinity receptor for substance P [neurokinin (NK) 1 receptor], the expression of which is greatly increased by RSV. This up-regulation presumably occurs at the gene expression level, as NK1 receptor mRNA levels increase substantially during RSV infection. We have also shown that T lymphocyte subpopulations within the bronchial-associated lymphoid tissue in the lungs of RSV-infected rats express high levels of the NK1 receptor. As a consequence stimulation of the sensory nerves by any airborne irritant has the potential of causing a new inflammatory cycle mediated by NK1 receptor-expressing T lymphocytes attracted into the airways and activated by substance P. This mechanism may establish important neuroimmune interactions, which undergo long term dysregulation after RSV infection and predispose to airway inflammation and hyperreactivity. Finally our most recent studies show that RSV infection promotes a large increase in the expression of nerve growth factor (NGF) and neurotrophin receptors. RSV-induced release of NGF leads to short and long term changes in the distribution and reactivity of sensory nerves across the respiratory tract, participating to exaggerated inflammatory reactions during and after the infection. NGF and its receptors may also amplify other immunoinflammatory and neuronal pathways contributing to airway inflammation and hyperreactivity. On the basis of these observations, we postulate that changes of neurotrophin expression in the respiratory tract may represent an important link between early life viral infections and childhood asthma.

Neurotrophins Regulate Bone Marrow Stromal Cell IL-6 Expression through the MAPK Pathway

“…Increased expression or release of Substance-P following neurotrophic stimulation of cells has been described in diverse settings documenting its important role in the hematopoietic-neuro-immune axis in inflammation, as well as normal and malignant hematopoiesis[57]–[62]. Relevant to our model, Substance-P has been shown to participate in upregulation of inflammatory cytokines in fibroblastic cells[63], [64] and more recently in a model of increased IL-6, IL-1β, and TNF-α in a model of burn-induced lung injury[65].…”

Brain-derived neurotrophic factor in the airways

“…Separately, BDNF can enhance expression of other receptors or enhance synaptic transmission, again enhancing bronchoconstriction. For example, upregulated neurokinin receptor expression can occur as demonstrated with NGF (Piedimonte, 2003) as well as with BDNF (Meuchel et al, 2011). However, beyond this rudimentary understanding, there is much not known about how BDNF or other NTs can influence airway innervation and neuronal function, especially given that there is currently no clear cut information on the distribution of receptors (TrkB, p75NTR) in airway nerve endings.…”

“…Nonetheless, it is possible to speculate that certain mechanisms that are common to different airway diseases do exist and would therefore be important to identify and understand. Recent studies indicate that the family of growth factors called neurotrophins (NTs) that have pleiotropic effects may play such a role in the lung(Aven and Ai, 2013; Braun et al, 2000; Hoyle, 2003; Jacoby, 2004; Lommatzsch et al, 2003; Piedimonte, 2003; Prakash et al, 2010; Renz et al, 2004; Rochlitzer et al, 2006; Taylor-Clark and Undem, 2006; Yao et al, 2006). While the NT family consists of different members, brain-derived neurotrophic factor (BDNF) is emerging as a particularly important player in the lung or airways (Lommatzsch et al, 2003; Prakash et al, 2010; Yao et al, 2006).…”

cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle

“…These data suggest a prominent role for BDNF in local control of airway structure and function. However, the role of BDNF in developing airway is still emerging [23, 29, 30]. In this regard, we have previously shown that moderate hyperoxia increases intracellular ASM BDNF, and enhances TrkB-mediated pro-contractile effects of BDNF on ASM, suggesting that BDNF is a key player in hyperoxia-induced increase of tone and reactivity of developing airway.…”