Neuronal modulation of lung injury induced by polymeric hexamethylene diisocyanate in mice.

Abstract

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.

• Authors: Chun-Ting Lee, Halet G Poovey, Roy J Rando, Gary W Hoyle
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 224 Issue 1 Pg. 19-28 (Oct 01 2007) ISSN: 0041-008X [Print] United States
• PMID: 17673270 (Publication Type: Journal Article)

Chemical References

• Antimetabolites
• Cyanates
• Isocyanates
• Receptors, Nerve Growth Factor
• Receptors, Tachykinin
• Scgb1a1 protein, mouse
• 1,6-hexamethylene diisocyanate
• Uteroglobin
• Cyclic AMP
• Bromodeoxyuridine

Topics

• Animals
• Antimetabolites
• Bromodeoxyuridine
• Cell Count
• Cell Proliferation (drug effects)
• Cyanates (toxicity)
• Cyclic AMP (metabolism)
• Epithelium (pathology)
• Gene Expression (drug effects)
• Immunohistochemistry
• Inflammation (chemically induced, pathology)
• Isocyanates
• Lung (innervation)
• Lung Diseases (chemically induced, pathology, physiopathology)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Neurons (physiology)
• Nuclease Protection Assays
• Rats
• Receptors, Nerve Growth Factor (deficiency, genetics)
• Receptors, Tachykinin (physiology)
• Respiratory Function Tests
• Therapeutic Irrigation
• Uteroglobin (deficiency, genetics)