Nerve growth factor: a novel mediator in asthma

Nerve growth factor (NGF) is known for years for its properties to induce neurite outgrowth. Its role in inflammation has recently been discovered. In this thesis the role of NGF in allergic asthma is shown. In chapter 2 we showed that NGF can induce airway hyperresponsiveness in guinea pigs. Simply injecting 8-80 ng NGF intravenously resulted in an airway hyperresponsiveness within 1 hr after administration. Sensory nerves in the aiwarys signal to the central nervous system. A subtype of these neurons express tachykinins, e.g. substance P and neurokinin A. Tachykinins can induce airway hyperresponsiveness. It seems NGF acts by sensitizing the sensory neurons. A neurokinin-1 receptor antagonist can prevent the induction of airway hyperresponsiveness by NGF. The neurokinin-1 receptor is the preferred receptor for the ligand substance P. In chapter 3 we show that NGF can sensitize the sensory nerve endings, and this either results in the release of more substance P or sensitization of the neurokinin-1 receptor, but does not involve an increased synthesis of substance P. Furthermore, cannabinoids can prevent the NGF-induced hyperresponsiveness in isolated tracheal ring as well as in the guinea pig in vivo. Cannabinoids induce an inhibitory signal in sensory neurons and thereby proof again that sensory nerve endings are involved in the induction of airway hyperresponsiveness by NGF. In a model for allergic asthma, using ovalbumin as an allergen, antibodies against NGF can prevent the acutely induced bronchoconstriction by inhalation of ovalbumin (chapter 4). This model for allergic asthma shows airway hyperresponsiveness as well, and this coincides with an increased content of tachykinins in the sensory neuronal cell bodies. In chapter 5 we show that this coincides with an increase in NGF in the airways as well. When the signal transduction pathway of the high affinity receptor for NGF, trkA, is blocked, the airway hyperresponsiveness can be prevented. Furthermore, the increase in substance P in the airways and neurons is prevented as well. Neurons as well as immune cells can release NGF. One of these cells is the mast cell. It has been suggested sensory neurons and mast cells interact. In chapter 6 we co-cultured bone marrow derived mast cells and dorsal root ganglion neurons to study whether these cells would affect each others function. The cells specifically adhered to each other. They only affect each other's function, though this seems not to be of any significant physiological importance. Concluding, NGF affects airway function by affecting sensory nerve function. This thesis shows NGF is involved in the development of airway pathology in a model for allergic asthma. This could lead to the development of a new class of therapeutics against allergic asthma