Contribution of neuroimmune mechanisms to airway inflammation and remodeling during and after respiratory syncytial virus infection.
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.
Piedimonte
Giovanni
G
Department of Pediatrics, Batchelor Children's Research Institute, University of Miami School of Medicine, 1580 NW Tenth Avenue, Miami, FL 33136, USA. gpiedimo@med.miami.edu
D000818:Animals; D001249:Asthma / Q000209:etiology*; D002199:Capillary Permeability; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008168:Lung / Q000294:innervation*; D009130:Muscle, Smooth / Q000502:physiology; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000494:pharmacology; D009473:Neuronal Plasticity; D011014:Pneumonia / Q000503:physiopathology*; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000503:physiopathology*; D018113:Respiratory Syncytial Virus, Human / Q000472:pathogenicity*; D012307:Risk Factors; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
D009414:Nerve Growth Factors; D018040:Receptors, Neurokinin-1; D013373:Substance P