Bronchiolite e Asma nel Bambino – Rome 2001
The Mechanisms of the Evolution from Bronchiolitis to Childhood
Asthma: Epidemiological, Cellular and Molecular Aspects
Giovanni Piedimonte, M.D.
Professor of Pediatrics, Medicine and Molecular/Cellular Pharmacology
Director, Pediatric Pulmonology and Cystic Fibrosis Center
University of Miami School of Medicine
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 neuro-immune
responses may be in play.
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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 when compared with 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 (NK1 receptor), whose expression 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-lymphocytes subpopulations within the bronchial-associated lymphoid tissue
(BALT) 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 Tlymphocytes attracted into the airways and activated by substance P. This mechanism
may establish important neuro-immune interactions, which undergo long-term
dysregulation following 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 may lead 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
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may also amplify other immuno-inflammatory and neuronal pathways contributing to
airway inflammation and hyperreactivity. Based on 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.
Suggested further reading
Piedimonte, G., M. M. Rodriguez, K. A. King, S. McLean, X. Jiang. 1999. Respiratory
syncytial virus upregulates expression of the substance P receptor in rat lungs, American
Journal of Physiology (Lung Cellular and Molecular Physiology) 277:L831-L840.
Piedimonte, G., K. A. King, N. L. Holmgren, P. J. Bertrand, M. M. Rodriguez, R. L.
Hirsch. 2000. A humanized monoclonal antibody against respiratory syncytial virus
(palivizumab) inhibits RSV-induced neurogenic-mediated inflammation in rat airways,
Pediatric Research 47:351-356.
King, K. A., C. Hu, M. M. Rodriguez, R. Romaguera, X. Jiang, and G. Piedimonte. 2001.
Exaggerated neurogenic inflammation and substance P receptor upregulation in RSVinfected weanling rats, American Journal of Respiratory Cell and Molecular Biology 24:
101-107.
Piedimonte, G. 2001. Neural mechanisms of respiratory syncytial virus-induced
inflammation and prevention of respiratory syncytial virus sequelae, American Journal of
Respiratory and Critical Care Medicine 163:S18-S21.
Piedimonte, G. 2001. Origins of reactive airways disease in early life: Do viral infections
play a role?, Acta Paediatrica, in press.
Piedimonte, G. 2001. Neuro-immune interactions in respiratory syncytial virus - infected
airways, Pediatric Infectious Disease Journal, in press.
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