NK1-receptor activation prevents hydrocarbon-induced lung injury in mice.

Recent evidence suggests that neurokinin (NK)-receptor activation may have a protective role in maintaining lung integrity when challenged by airborne toxicants such as sulfur dioxide, ozone, acrolein, or hydrocarbons. To investigate the effect of NK1-receptor activation on hydrocarbon-induced lung injury, B6.A.D. (Ahr d/Nats) mice received subchronic exposures to JP-8 jet fuel (JP-8). Lung injury was assessed by the analysis of pulmonary physiology, bronchoalveolar lavage fluid, and morphology. Hydrocarbon exposure to target JP-8 concentrations of 50 mg/m3, with saline treatment, was characterized by enhanced respiratory permeability to 99mTc-labeled diethylenetriaminepentaacetic acid, alveolar macrophage toxicity, and bronchiolar epithelial damage. Mice administered [Sar9,Met(O2)11]substance P, an NK1-receptor agonist, after each JP-8 exposure had the appearance of normal pulmonary values and tissue morphology. In contrast, endogenous NK1-receptor antagonism by CP-96345 administration exacerbated JP-8-enhanced permeability, alveolar macrophage toxicity, and bronchiolar epithelial injury. These data indicate that NK1-receptor activation may have a protective role in preventing the development of hydrocarbon-induced lung injury, possibly through the modulation of bronchiolar epithelial function.

[1]  R. Pauwels,et al.  Effect of inhaled substance P and neurokinin A on the airways of normal and asthmatic subjects. , 1987, Thorax.

[2]  E. Naline,et al.  Evidence for functional tachykinin NK1 receptors on human isolated small bronchi. , 1996, The American journal of physiology.

[3]  R. Robledo,et al.  Immunotoxicological Effects of Jp-8 Jet Fuel Exposure , 1997, Toxicology and industrial health.

[4]  F. Bazzoni,et al.  Activation of human neutrophils by substance P. Effect on oxidative metabolism, exocytosis, cytosolic Ca2+ concentration and inositol phosphate formation. , 1988, Journal of immunology.

[5]  M. King,et al.  Resorptive clearance and transepithelial potential difference in capsaicin-treated F344 rats. , 1990, Journal of applied physiology.

[6]  W. Weber,et al.  2-aminofluorene-hepatic DNA adducts in congenic mouse lines differing in Ah responsiveness. , 1990, Carcinogenesis.

[7]  A. Sterner-Kock,et al.  Neonatal capsaicin treatment increases the severity of ozone-induced lung injury. , 1996, American journal of respiratory and critical care medicine.

[8]  E. Christian,et al.  Protective role for neuropeptides in acute pulmonary response to acrolein in guinea pigs. , 1993, Journal of applied physiology.

[9]  E. Goetzl,et al.  Immunochemical localization of type I VIP receptor and NK-1-type substance P receptor in rat lung. , 1995, The American journal of physiology.

[10]  H. Magnussen,et al.  Migration and proliferation of guinea pig and human airway epithelial cells in response to tachykinins. , 1995, The American journal of physiology.

[11]  J. Voigt,et al.  Localization, distribution, and induction of xenobiotic-metabolizing enzymes and aryl hydrocarbon hydroxylase activity within lung. , 1990, Pharmacology & therapeutics.

[12]  K. Kitto,et al.  CP-96,345, which inhibits [3H] substance P binding, selectively inhibits the behavioral response to intrathecally administered N-methyl-D-aspartate, but not substance P, in the mouse. , 1997, The Journal of pharmacology and experimental therapeutics.

[13]  John Pfaff,et al.  Inhalation exposure to jp‐8 jet fuel alters pulmonary function and substance p levels in fischer 344 rats , 1995, Journal of applied toxicology : JAT.

[14]  P. Barnes,et al.  Characterization and autoradiographic mapping of [3H]CP96,345, a nonpeptide selective NK1 receptor antagonist in guinea pig lung , 1995, Peptides.

[15]  P. Rangachari,et al.  Effects of tachykinins on the electrical activity of isolated canine tracheal epithelium: an exploratory study , 1985, Regulatory Peptides.

[16]  S. Nakanishi.  Mammalian tachykinin receptors. , 1991, Annual review of neuroscience.

[17]  J. Crapo,et al.  Morphometry of the Alveolar Region of the Lung , 1985 .

[18]  A. Bonham,et al.  Sidestream smoke exposure enhances rapidly adapting receptor responses to substance P in young guinea pigs. , 1996, Journal of applied physiology.

[19]  A. Didier,et al.  Substance P and alveolar macrophages: effects on oxidative metabolism and eicosanoid production , 1995, Allergy.

[20]  Raymond F. Robledo Mark L. Witten.  ACUTE PULMONARY RESPONSE TO INHALED JP-8 JET FUEL AEROSOL IN MICE , 1998 .

[21]  T. Mccaffrey,et al.  Signal transduction mechanisms in substance P-mediated ciliostimulation. , 1995, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[22]  K. Chung,et al.  Effect of CP-96,345, a non-peptide NK1 receptor antagonist, against substance P-, bradykinin- and allergen-induced airway microvascular leakage and bronchoconstriction in the guinea pig. , 1993, European journal of pharmacology.

[23]  K. Yoshioka,et al.  Neurotransmitter functions of mammalian tachykinins. , 1993, Physiological reviews.

[24]  J. Paulauskis,et al.  Substance P content and preprotachykinin gene-I mRNA expression in a rat model of chronic bronchitis. , 1996, American journal of respiratory cell and molecular biology.

[25]  S. Scharf,et al.  Pulmonary mechanics in dogs given different doses of kerosene intratracheally. , 2015, The American review of respiratory disease.

[26]  J. S. Kim,et al.  Proliferation and repair of guinea pig tracheal epithelium after neuropeptide depletion and injury in vivo. , 1997, The American journal of physiology.

[27]  J. Rabovsky,et al.  In vitro effects of straight-chain alkanes (n-hexane through n-dodecane) on rat liver and lung cytochrome P-450. , 1986, Journal of toxicology and environmental health.

[28]  S. Guard,et al.  The interaction of the NK1 receptor antagonist CP‐96,345 with L‐type calcium channels and its functional consequences , 1993, British journal of pharmacology.

[29]  B. Nilsson,et al.  Substance P and vasoactive intestinal peptide influence polyamine metabolism in salivary glands of the rat. , 1989, Acta physiologica Scandinavica.

[30]  C. Pothoulakis,et al.  Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  P. Barnes,et al.  Effects of tachykinins on mucus secretion in human bronchi in vitro. , 1989, European journal of pharmacology.

[32]  R C Lantz,et al.  Neutral Endopeptidase (NEP) and Its Role in Pathological Pulmonary Change With Inhalation Exposure To JP-8 Jet Fuel , 1996, Toxicology and industrial health.