JF Molinari, M Scuri, WR Moore, J Clark, R Tanaka and WM Abraham
Division of Pulmonary Disease, University of Miami at Mount Sinai Medical Center, Florida 33140, USA.

Allergen-induced bronchoconstriction involves mast cell activation. Tryptase is a mast cell serine protease that is released during this process, but little is known about the action of tryptase in the airway. The purpose of this study was to determine: (1) if aerosolized tryptase causes bronchoconstriction, and (2) the mechanism by which this occurs. We measured mean pulmonary flow resistance (RL) in five allergic sheep before and after consecutive inhalations of 100 and 500 ng tryptase (in 2 ml total volume). Inhaled tryptase at 100 and 500 ng increased RL (mean +/- SE) by 33 +/- 12 and 122 +/- 8% (p < 0.05) over baseline. The response was reproducible upon repeat challenges. These studies were repeated in the same animals after pretreatment with aerosolized APC 366 (9 mg/3 ml), a specific tryptase inhibitor. In APC- 366-treated sheep, tryptase increased RL by 10 +/- 3 and 6 +/- 2% (p < 0.05 versus control values) at 100 and 500 ng, respectively. The response to tryptase was also blocked by pretreating the sheep intravenously with the histamine H1-antagonist chlorpheniramine (2 mg/kg), in which RL increased only 5 +/- 4 and 7 +/- 6% after 100 and 500 ng tryptase. APC 366, however, did not block histamine-induced bronchoconstriction. Consistent with these findings was the observation that segmental bronchial challenge with tryptase (1 microgram) resulted in a significant increase in histamine levels in bronchoalveolar lavage. Inhaled tryptase (500 ng) also caused airway hyperresponsiveness to aerosolized carbachol 2 h after tryptase challenge. This tryptase-induced airway hyperresponsiveness could be blocked either by pretreating the sheep with APC 366 (30 min before challenge) or by treating the sheep 30 min after challenge. These results indicate that inhaled tryptase causes bronchoconstriction and airway hyperresponsiveness in allergic sheep by an event that may involve mast cell activation.

This article has been cited by other articles:

				P. Bradding Mast cell regulation of airway smooth muscle function in asthma Eur. Respir. J., May 1, 2007; 29(5): 827 - 830. [Full Text] [PDF]

				Y. Fukuoka and L. B. Schwartz The B12 Anti-Tryptase Monoclonal Antibody Disrupts the Tetrameric Structure of Heparin-Stabilized beta-Tryptase to Form Monomers That Are Inactive at Neutral pH and Active at Acidic pH. J. Immunol., March 1, 2006; 176(5): 3165 - 3172. [Abstract] [Full Text] [PDF]

				T. Trian, P.-O. Girodet, O. Ousova, R. Marthan, J. M. Tunon-de-Lara, and P. Berger RNA Interference Decreases PAR-2 Expression and Function in Human Airway Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., January 1, 2006; 34(1): 49 - 55. [Abstract] [Full Text] [PDF]

				S.-W. Oh, C. I. Pae, D.-K. Lee, F. Jones, G. K. S. Chiang, H.-O. Kim, S.-H. Moon, B. Cao, C. Ogbu, K.-W. Jeong, et al. Tryptase Inhibition Blocks Airway Inflammation in a Mouse Asthma Model J. Immunol., February 15, 2002; 168(4): 1992 - 2000. [Abstract] [Full Text] [PDF]

				W. M. Abraham Tryptase: potential role in airway inflammation and remodeling Am J Physiol Lung Cell Mol Physiol, February 1, 2002; 282(2): L193 - L196. [Full Text] [PDF]

				C. P. SOMMERHOFF Mast Cell Tryptases and Airway Remodeling Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): S52 - 58. [Abstract] [Full Text] [PDF]

				J. Hallgren, D. Spillmann, and G. Pejler Structural Requirements and Mechanism for Heparin-induced Activation of a Recombinant Mouse Mast Cell Tryptase, Mouse Mast Cell Protease-6. FORMATION OF ACTIVE TRYPTASE MONOMERS IN THE PRESENCE OF LOW MOLECULAR WEIGHT HEPARIN J. Biol. Chem., November 9, 2001; 276(46): 42774 - 42781. [Abstract] [Full Text] [PDF]

				P. Berger, D.-W. Perng, H. Thabrew, S. J. Compton, J. A Cairns, A. R. McEuen, R. Marthan, J.-M. Tunon De Lara, and A. F. Walls Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells J Appl Physiol, September 1, 2001; 91(3): 1372 - 1379. [Abstract] [Full Text] [PDF]

				W. M. ABRAHAM, A. GILL, A. AHMED, M. W. SIELCZAK, I. T. LAUREDO, Y. BOTINNIKOVA, K.-C. LIN, B. PEPINSKY, D. R. LEONE, R. R. LOBB, et al. A Small-Molecule, Tight-binding Inhibitor of the Integrin alpha 4beta 1 Blocks Antigen-induced Airway Responses and Inflammation in Experimental Asthma in Sheep Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 603 - 611. [Abstract] [Full Text] [PDF]

				T. Kobayashi, T. Miura, T. Haba, M. Sato, I. Serizawa, H. Nagai, and K. Ishizaka An Essential Role of Mast Cells in the Development of Airway Hyperresponsiveness in a Murine Asthma Model J. Immunol., April 1, 2000; 164(7): 3855 - 3861. [Abstract] [Full Text] [PDF]

				S. He, M. D. A. Gaça, A. R. McEuen, and A. F. Walls Inhibitors of Chymase as Mast Cell-Stabilizing Agents: Contribution of Chymase in the Activation of Human Mast Cells J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 517 - 523. [Abstract] [Full Text]

				C. D. Wright, A. M. Havill, S. C. Middleton, M. A. Kashem, P. A. Lee, D. J. Dripps, T. G. O'Riordan, M. P. Bevilacqua, and W. M. Abraham Secretory Leukocyte Protease Inhibitor Prevents Allergen-Induced Pulmonary Responses in Animal Models of Asthma J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 1007 - 1014. [Abstract] [Full Text]

				P. J. Barnes, K. F. Chung, and C. P. Page Inflammatory Mediators of Asthma: An Update Pharmacol. Rev., December 1, 1998; 50(4): 515 - 596. [Abstract] [Full Text] [PDF]

				S. He, M. D. A. Gaça, and A. F. Walls A Role for Tryptase in the Activation of Human Mast Cells: Modulation of Histamine Release by Tryptase and Inhibitors of Tryptase J. Pharmacol. Exp. Ther., July 1, 1998; 286(1): 289 - 297. [Abstract] [Full Text]

				K. C. ELROD, W. R. MOORE, W. M. ABRAHAM, and R. D. TANAKA Lactoferrin, a Potent Tryptase Inhibitor, Abolishes Late-Phase Airway Responses in Allergic Sheep Am. J. Respir. Crit. Care Med., July 1, 1997; 156(2): 375 - 381. [Abstract] [Full Text]