JM Clark, WM Abraham, CE Fishman, R Forteza, A Ahmed, A Cortes, RL Warne, WR Moore and RD Tanaka
Department of Molecular Pharmacology, Arris Pharmaecutical Corporation, South San Francisco, California 94080, USA.

Tryptase, a mast cell serine protease, has been implicated in the pathophysiology of allergic asthma, but formal evidence to support this hypothesis has been limited by the lack of specific inhibitors for use in vivo. Therefore, in this study we examined the effects of two inhibitors of tryptase, APC 366 [N-(1-hydroxy-2-naphthoyl)-L-arginyl-L- prolinamide hydrochloride] and BABIM [bis(5-amidino-2- benzimidazolyl)methane] on antigen-induced early and late responses, airway responsiveness as measured by carbachol provocation, microvascular permeability as measured by bronchoalveolar lavage (BAL) albumin concentrations, and tissue eosinophilia from biopsies in allergic sheep. APC 366 and BABIM were administered by aerosol in all experiments. In vehicle control trials, antigen challenge resulted in peak early and late increases in specific lung resistance (SRL) of (mean +/- SE, n = 6) 259 +/- 30% and 183 +/- 27% over baseline, respectively. Treatment with APC 366 (9 mg/3 ml H2O given 0.5 h before, 4 h after, and 24 h after antigen challenge) slightly reduced the peak early response (194 +/- 41%), but significantly inhibited the late response (38 +/- 6%, p < 0.05 versus control trials). Twenty-four hours after challenge, APC 366 also completely blocked the antigen-induced airway hyperresponsiveness to inhaled carbachol observed in the control trial.(ABSTRACT TRUNCATED AT 250 WORDS)

This article has been cited by other articles:

				N. N. Trivedi, Q. Tong, K. Raman, V. J. Bhagwandin, and G. H. Caughey Mast Cell {alpha} and beta Tryptases Changed Rapidly during Primate Speciation and Evolved from {gamma}-Like Transmembrane Peptidases in Ancestral Vertebrates J. Immunol., November 1, 2007; 179(9): 6072 - 6079. [Abstract] [Full Text] [PDF]

				W. M. Abraham, A. Ahmed, I. Serebriakov, I. T. Lauredo, J. Bassuk, J. A. Adams, and M. A. Sackner Whole-Body Periodic Acceleration Modifies Experimental Asthma in Sheep Am. J. Respir. Crit. Care Med., October 1, 2006; 174(7): 743 - 752. [Abstract] [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]

				K. Page, V. S. Hughes, K. K. Odoms, K. E. Dunsmore, and M. B. Hershenson German Cockroach Proteases Regulate Interleukin-8 Expression via Nuclear Factor for Interleukin-6 in Human Bronchial Epithelial Cells Am. J. Respir. Cell Mol. Biol., March 1, 2005; 32(3): 225 - 231. [Abstract] [Full Text] [PDF]

				V. S. OSSOVSKAYA and N. W. BUNNETT Protease-Activated Receptors: Contribution to Physiology and Disease Physiol Rev, April 1, 2004; 84(2): 579 - 621. [Abstract] [Full Text] [PDF]

				S. He, A. Aslam, M. D. A. Gaca, Y. He, M. G. Buckley, M. D. Hollenberg, and A. F. Walls Inhibitors of Tryptase as Mast Cell-Stabilizing Agents in the Human Airways: Effects of Tryptase and Other Agonists of Proteinase-Activated Receptor 2 on Histamine Release J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 119 - 126. [Abstract] [Full Text]

				H.-W. Wang, H. P. McNeil, A. Husain, K. Liu, N. Tedla, P. S. Thomas, M. Raftery, G. C. King, Z. Y. Cai, and J. E. Hunt {delta} Tryptase Is Expressed in Multiple Human Tissues, and a Recombinant Form Has Proteolytic Activity J. Immunol., November 1, 2002; 169(9): 5145 - 5152. [Abstract] [Full Text] [PDF]

				F. Schmidlin, S. Amadesi, K. Dabbagh, D. E. Lewis, P. Knott, N. W. Bunnett, P. R. Gater, P. Geppetti, C. Bertrand, and M. E. Stevens Protease-Activated Receptor 2 Mediates Eosinophil Infiltration and Hyperreactivity in Allergic Inflammation of the Airway J. Immunol., November 1, 2002; 169(9): 5315 - 5321. [Abstract] [Full Text] [PDF]

				C. E. Brightling, P. Bradding, F. A. Symon, S. T. Holgate, A. J. Wardlaw, and I. D. Pavord Mast-Cell Infiltration of Airway Smooth Muscle in Asthma N. Engl. J. Med., May 30, 2002; 346(22): 1699 - 1705. [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]

				J. K. Brown, C. A. Jones, L. A. Rooney, G. H. Caughey, and I. P. Hall Tryptase's potent mitogenic effects in human airway smooth muscle cells are via nonproteolytic actions Am J Physiol Lung Cell Mol Physiol, February 1, 2002; 282(2): L197 - L206. [Abstract] [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]

				F. SCHMIDLIN, S. AMADESI, R. VIDIL, M. TREVISANI, N. MARTINET, G. CAUGHEY, M. TOGNETTO, G. CAVALLESCO, C. MAPP, P. GEPPETTI, et al. Expression and Function of Proteinase-activated Receptor 2 in Human Bronchial Smooth Muscle Am. J. Respir. Crit. Care Med., October 1, 2001; 164(7): 1276 - 1281. [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]

				P. Berger, J. M. Tunon-De-Lara, J.-P. Savineau, and R. Marthan Signal Transduction in Smooth Muscle: Selected Contribution: Tryptase-induced PAR-2-mediated Ca2+ signaling in human airway smooth muscle cells J Appl Physiol, August 1, 2001; 91(2): 995 - 1003. [Abstract] [Full Text] [PDF]

				W. W. Busse and R. F. Lemanske Asthma N. Engl. J. Med., February 1, 2001; 344(5): 350 - 362. [Full Text] [PDF]

				M. Scuri, R. Forteza, I. Lauredo, J. R. Sabater, Y. Botvinnikova, L. Allegra, and W. M. Abraham Inhaled porcine pancreatic elastase causes bronchoconstriction via a bradykinin-mediated mechanism J Appl Physiol, October 1, 2000; 89(4): 1397 - 1402. [Abstract] [Full Text] [PDF]

				F. L. M. RICCIARDOLO, M. STEINHOFF, S. AMADESI, R. GUERRINI, M. TOGNETTO, M. TREVISANI, C. CREMINON, C. BERTRAND, N. W. BUNNETT, L. M. FABBRI, et al. Presence and Bronchomotor Activity of Protease-Activated Receptor-2 in Guinea Pig Airways Am. J. Respir. Crit. Care Med., May 1, 2000; 161(5): 1672 - 1680. [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]

				M. Pallaoro, M. S. Fejzo, L. Shayesteh, J. L. Blount, and G. H. Caughey Characterization of Genes Encoding Known and Novel Human Mast Cell Tryptases on Chromosome 16p13.3 J. Biol. Chem., February 5, 1999; 274(6): 3355 - 3362. [Abstract] [Full Text] [PDF]

				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. J. Compton, J. A. Cairns, S. T. Holgate, and A. F. Walls The Role of Mast Cell Tryptase in Regulating Endothelial Cell Proliferation, Cytokine Release, and Adhesion Molecule Expression: Tryptase Induces Expression of mRNA for IL-1{beta} and IL-8 and Stimulates the Selective Release of IL-8 from Human Umbilical Vein Endothelial Cells J. Immunol., August 15, 1998; 161(4): 1939 - 1946. [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]

				C. Huang, G. W. Wong, N. Ghildyal, M. F. Gurish, A. Sali, R. Matsumoto, W.-T. Qiu, and R. L. Stevens The Tryptase, Mouse Mast Cell Protease 7, Exhibits Anticoagulant Activity in Vivo and in Vitro Due to Its Ability to Degrade Fibrinogen in the Presence of the Diverse Array of Protease Inhibitors in Plasma J. Biol. Chem., December 12, 1997; 272(50): 31885 - 31893. [Abstract] [Full Text] [PDF]

				W. M. ABRAHAM, A. AHMED, M. W. SIELCZAK, M. NARITA, T. ARRHENIUS, and M. J. ELICES Blockade of Late-phase Airway Responses and Airway Hyperresponsiveness in Allergic Sheep with a Small-molecule Peptide Inhibitor of VLA-4 Am. J. Respir. Crit. Care Med., September 1, 1997; 156(3): 696 - 703. [Abstract] [Full Text] [PDF]

				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]

				M. Molino, E. S. Barnathan, R. Numerof, J. Clark, M. Dreyer, A. Cumashi, J. A. Hoxie, N. Schechter, M. Woolkalis, and L. F. Brass Interactions of Mast Cell Tryptase with Thrombin Receptors and PAR-2 J. Biol. Chem., February 14, 1997; 272(7): 4043 - 4049. [Abstract] [Full Text] [PDF]

				G. W. Wong, S. Yasuda, M. S. Madhusudhan, L. Li, Y. Yang, S. A. Krilis, A. Sali, and R. L. Stevens Human Tryptase epsilon (PRSS22), a New Member of the Chromosome 16p13.3 Family of Human Serine Proteases Expressed in Airway Epithelial Cells J. Biol. Chem., December 28, 2001; 276(52): 49169 - 49182. [Abstract] [Full Text] [PDF]