Hyperinnervation of the Airways in Transgenic Mice Overexpressing Nerve Growth Factor

Abstract

Neuropeptides released from sensory nerve endings are potential mediators of airway inflammation in asthma and lung injury induced by inhalation of respiratory irritants. To develop an in vivo model for assessing the contribution of neurogenic inflammation in these processes, we have generated transgenic mice with altered innervation of the lung. To generate mice with an increased innervation of the airways, we placed the gene that encodes nerve growth factor (NGF) under control of the lung-specific Clara-cell secretory protein (CCSP) promoter. Two lineages of CCSP-NGF transgenic mice overexpressed NGF in the lung and developed a hyperinnervation of the airways. Immunohistochemistry for substance P, a substance P enzyme immunoassay, and catecholamine histofluorescence indicated that both tachykinin-containing sensory fibers and sympathetic fibers were increased around the airways of CCSP-NGF mice. Treatment of CCSP-NGF mice with the sympathetic-specific neurotoxin 6-hydroxydopamine (6-OHDA) eliminated the sympathetic component of the airway innervation, leaving a specific hyperinnervation by tachykinin-containing sensory fibers. CCSP-NGF mice were more sensitive than normal mice to capsaicin-induced increases in respiratory system resistance, demonstrating that the increased sensory innervation led to a change in airway function. We conclude that NGF overexpression from a lung-specific promoter produces anatomic and functional changes in lung innervation, and that CCSP-NGF mice will be useful for studying the role of neurogenic inflammation in airway disease.

The role of sensory nerve endings in nerve growth factor‐induced airway hyperresponsiveness to histamine in guinea‐pigs

“…The p75 low anity NGF receptor is also shown to be responsible for an upregulation in tachykinin content in sensory nerves (Lee et al, 1992). Hoyle et al (1998) showed that transgenic mice over-expressing NGF in the airways develop a hyperinnervation of the airways and an increase in substance P. Other studies reported that long-term NGF exposure induces upregulation of substance P in sensory nerves, though this was not studied in the airways (e.g. Lindsay & Harmar, 1989).…”

Expression and Role of the TrkA Receptor in Pulmonary Inflammatory Diseases

“…In vitro, NGF activates the TrkA receptor to induce migration of pulmonary fibroblasts (Kohyama et al, 2002) and regulation of extracellular matrix synthesis (Khan et al, 2002;Takahashi et al, 2000). These results therefore suggest a role for the TrkA receptor in NGF-induced airway sub-epithelial fibrosis in vivo (Hoyle et al, 1998). We also reported that NGF induces proliferation of the airway smooth muscle through activation of the TrkA receptor and may therefore participate to hyperplasia of the smooth muscle layer in vivo (Freund-Michel et al, 2006).…”

“…NGF also displays its role of growth factor on airway nerves, in particular on sensory airway nerves (Hoyle et al, 1998), and is able to stimulate other airway structural cells such as pulmonary fibroblasts or airway smooth muscle cells (Freund-Michel & Frossard, 2008a). Some of these effects involve activation of the TrkA receptor expressed on these cells (Fig.…”

Human lung fibroblasts secrete nerve growth factor: effect of inflammatory cytokines and glucocorticoids

“…As evidenced from animal studies, NGF may contribute to the development of airway hyperresponsiveness [3 -5] and to an increased sensory and sympathetic innervation in the lung [4], and it may evoke a phenotypic change of airway sensory neurones [4]. NGF also has a profound effect on cells of the immune system, many of which are critically important in the development of pulmonary inflammation and asthma-related symptoms.…”