Neuronal modulation of lung injury induced by polymeric hexamethylene diisocyanate in mice.
1,6-Hexamethylene diisocyanate biuret trimer (HDI-BT) is a nonvolatile isocyanate that is a component of polyurethane spray paints. HDI-BT is a potent irritant that when inhaled stimulates sensory nerves of the respiratory tract. The role of sensory nerves in modulating lung injury following inhalation of HDI-BT was assessed in genetically manipulated mice with altered innervation of the lung. Knockout mice with a mutation in the low-affinity nerve growth factor receptor (NGFR), which have decreased innervation by nociceptive nerve fibers, and transgenic mice expressing nerve growth factor (NGF) from the lung-specific Clara cell secretory protein (CCSP) promoter, which have increased innervation of the airways, were exposed to HDI-BT aerosol and evaluated at various times after exposure. NGFR knockout mice exhibited significantly more, and CCSP-NGF transgenic mice exhibited significantly less injury and inflammation compared with wild-type mice, indicative of a protective effect of nociceptive nerves on the lung following HDI-BT inhalation. Transgenic mice overexpressing the tachykinin 1 receptor (Tacr1) in lung epithelial cells also showed less severe injury and inflammation compared with wild-type mice after HDI-BT exposure, establishing a role for released tachykinins acting through Tacr1 in mediating at least part of the protective effect. Treatment of lung fragments from Tacr1 transgenic mice with the Tacr1 ligand substance P resulted in increased cAMP accumulation, suggesting this compound as a possible signaling mediator of protective effects on the lung following nociceptive nerve stimulation. The results indicate that sensory nerves acting through Tacr1 can exert protective or anti-inflammatory effects in the lung following isocyanate exposure.
Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Department of Medicine, SL-9, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Chun-Ting
CT
Lee
Halet G
HG
Poovey
Roy J
RJ
Rando
Gary W
GW
Hoyle
D000818:Animals; D000963:Antimetabolites; D001973:Bromodeoxyuridine; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D003485:Cyanates / Q000633:toxicity*; D000242:Cyclic AMP / Q000378:metabolism; D004848:Epithelium / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D017953:Isocyanates; D008168:Lung / Q000294:innervation; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D023282:Nuclease Protection Assays; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics; D018039:Receptors, Tachykinin / Q000502:physiology; D012129:Respiratory Function Tests; D007507:Therapeutic Irrigation; D014598:Uteroglobin / Q000172:deficiency / Q000235:genetics
D000963:Antimetabolites; D003485:Cyanates; D017953:Isocyanates; D017475:Receptors, Nerve Growth Factor; D018039:Receptors, Tachykinin; C556390:Scgb1a1 protein, mouse; C015262:1,6-hexamethylene diisocyanate; D014598:Uteroglobin; D000242:Cyclic AMP; D001973:Bromodeoxyuridine