Overview of Animal Models of Asthma

Brendan J. Canning1

1 Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.25
DOI:  10.1002/0471141755.ph0525s16
Online Posting Date:  May, 2002
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

Asthma is an inflammatory disease characterized by airways obstruction, airways hyperresponsiveness, excessive mucous secretion and cough. Guinea pig airways display many anatomical, physiological and pharmacological attributes of human airways, making this species ideal for modeling the asthmatic condition. This unit provides an overview of animal models of asthma, including definitions, descriptions of available animal models, and discussion of numerous critical issues to consider before designing a model to study this complex disease.

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • Airways Obstruction
  • Airways Hyperresponsiveness
  • Airways Inflammation
  • Literature Cited
  • Figures
  • Tables
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
   Abraham, W.M., Lanes, S., Stevenson, J.S., and Yerger, L.D. 1986. Effect of an inhaled glucocorticosteroid (budesonide) on post‐antigen induced increases in airway responsiveness. Bull. Eur. Physiopathol. Respir. 22:387‐392.
   Abraham, W.M., Stevenson, J.S., Chapman, G.A., Tallent, M.W., and Jackowski, J. 1987. The effect of nedocromil sodium and cromolyn sodium on antigen‐induced responses in allergic sheep in vivo and in vitro. Chest 92:913‐917.
   Abraham, W.M., Stevenson, J.S., and Garrido, R. 1989. A possible role for PAF in allergen‐induced late responses: Modification by a selective antagonist. J. Appl. Physiol. 66:2351‐2357.
   Abraham, W.M., Ahmed, A., Cortes, A., Sielczak, M.W., Hinz, W., Bouska, J., Lanni, C., and Bell, R.L. 1992. The 5‐lipoxygenase inhibitor zileuton blocks antigen‐induced late airway responses, inflammation and airway hyperresponsiveness in allergic sheep. Eur. J. Pharmacol. 217:119‐126.
   Abraham, W.M., Gill, A., Ahmed, A., Sielczak, M.W., Lauredo, I.T., Botinnikova, Y., Lin, K.C., Pepinsky, B., Leone, D.R., Lobb, R.R., and Adams, S.P. 2000. A small‐molecule, tight‐binding inhibitor of the integrin alpha(4)beta(1) blocks antigen‐induced airway responses and inflammation in experimental asthma in sheep. Am. J. Respir. Crit. Care Med. 162:603‐611.
   Aizawa, H., Shigyo, M., Nogami, H., Hirose, T., and Hara, N. 1996. BAY u3405, a thromboxane A2 antagonist, reduces bronchial hyperresponsiveness in asthmatics. Chest 109:338‐342.
   Babu, K.S. and Salvi, S.S. 2000. Aspirin and asthma. Chest 118:1470‐1476.
   Barnette, M.S. 1999. Phosphodiesterase 4 (PDE4) inhibitors in asthma and chronic obstructive pulmonary disease (COPD). Prog. Drug Res. 53:193‐229.
   Becker, A.B., Black, C., Lilley, M.K., Bajwa, K., Ford‐Hutchinson, A.W., Simons, F.E., and Tagari, P. 1995. Antiasthmatic effects of a leukotriene biosynthesis inhibitor (MK‐0591) in allergic dogs. J. Appl. Physiol. 78:615‐622.
   Borish, L.C., Nelson, H.S., Lanz, M.J., Claussen, L., Whitmore, J.B., Agosti, J.M., and Garrison, L. 1999. Interleukin‐4 receptor in moderate atopic asthma. A phase I/II randomized, placebo‐controlled trial. Am. J. Respir. Crit. Care Med. 160:1816‐1823.
   Bosken, C.H., Hunt, W.C., Lambert, W.E., and Samet, J.M. 2000. A parental history of asthma is a risk factor for wheezing and nonwheezing respiratory illnesses in infants younger than 18 months of age. Am. J. Respir. Crit. Care Med. 161:1810‐1815.
   Bousquet, J., Chanez, P., Lacoste, J.Y., Barneon, G., Ghavanian, N., Enander, I., Venge, P., Ahlstedt, S., Simony‐Lafontaine, J., Godard, P., and Michel, F.‐B. 1990. Eosinophilic inflammation in asthma. New Engl. J. Med. 323:1033‐1039.
   Bousquet, J., Jeffery, P.K., Busse, W.W., Johnson, M., and Vignola, A.M. 2000. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am. J. Respir. Crit. Care Med. 161:1720‐1745.
   Brown, R.H., Mitzner, W., and Wagner, E.M. 1997. Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo. J. Appl. Physiol. 83:366‐370.
   Calhoun, W.J., Lavins, B.J., Minkwitz, M.C., Evans, R., Gleich, G.J., and Cohn, J. 1998. Effect of zafirlukast (Accolate) on cellular mediators of inflammation: Bronchoalveolar lavage fluid findings after segmental antigen challenge. Am. J. Respir. Crit. Care Med. 157:1381‐1389.
   Canning, B.J. 1997. Potential role of tachykinins in inflammatory diseases. J. Allergy Clin. Immunol. 99:579‐582.
   Canning, B.J. and Widdicombe, J.G. 2001. Innervation of the airways. Respir. Physiol. 125:1‐2.
   Cerrina, J., Labat, C., Haye‐Legrande, I., Raffestin, B., Benveniste, J., and Brink, C. 1989. Human isolated bronchial muscle preparations from asthmatic patients: Effects of indomethacin and contractile agonists. Prostaglandins 37:457‐469.
   Chung, K.F., Aizawa, H., Leikauf, G.D., Ueki, I.F., Evans, T.W., and Nadel, J.A. 1986. Airway hyperresponsiveness induced by platelet‐activating factor: Role of thromboxane generation. J. Pharmacol. Exp. Ther. 236:580‐584.
   Church, M.K., Hutson, P.A., and Holgate, S.T. 1993. Nedocromil sodium blocks the early and late phases of allergen challenge in a guinea pig model of asthma. J. Allergy Clin. Immunol. 92:177‐182.
   Cockcroft, D.W. 1997. Airway Responsiveness. In Asthma (P.J. Barnes, M.M. Grunstein, A.R. Leff, and A.J. Woolcock, eds.) pp. 1253‐1266. Lippincott‐Raven, Philadelphia.
   Corcoran, B.M., Foster, D.J., and Fuentes, V.L. 1995. Feline asthma syndrome: A retrospective study of the clinical presentation in 29 cats. J. Small Anim. Pract. 36:481‐488.
   Corry, D.B., Folkesson, H.G., Warnock, M.L., Erle, D.J., Matthay, M.A., Wiener‐Kronish, J.P., and Locksley, R.M. 1996. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J. Exp. Med. 183:109‐117.
   Coyle, A.J., Wagner, K., Bertrand, C., Tsuyuki, S., Bews, J., and Heusser, C. 1996. Central role of immunoglobulin (Ig) E in the induction of lung eosinophil infiltration and T helper 2 cell cytokine production: Inhibition by a non‐anaphylactogenic anti‐IgE antibody. J. Exp. Med. 183:1303‐1310.
   Crimi, E., Spanevello, A., Neri, M., Ind, P.W., Rossi, G.A., and Brusasco, V. 1998. Dissociation between airway inflammation and airway hyperresponsiveness in allergic asthma. Am. J. Respir. Crit. Care Med. 157:4‐9.
   Darowski, M.J., Hannon, V.M., and Hirshman, C.A. 1989. Corticosteroids decrease airway hyperresponsiveness in the Basenji‐Greyhound dog model of asthma. J. Appl. Physiol. 66:1120‐1126.
   Das, A.M., Williams, T.J., Lobb, R., and Nourshargh, S. 1995. Lung eosinophilia is dependent on IL‐5 and the adhesion molecules CD18 and VLA‐4, in a guinea‐pig model. Immunology 84:41‐46.
   De Bie, J.J., Henricks, P.A., Cruikshank, W.W., Hofman, G., Jonker, E.H., Nijkamp, F.P., and Van Oosterhout, A.J. 1998. Modulation of airway hyperresponsiveness and eosinophilia by selective histamine and 5‐HT receptor antagonists in a mouse model of allergic asthma. Br. J. Pharmacol. 124:857‐864.
   Diamant, Z., Hiltermann, J.T., van Rensen, E.L., Callenbach, P.M., Veselic‐Charvat, M., van der Veen, H., Sont, J.K., and Sterk, P.J. 1997. The effect of inhaled leukotriene D4 and methacholine on sputum cell differentials in asthma. Am. J. Respir. Crit. Care Med. 155:1247‐1253.
   Djukanovic, R., Roche, W.R., Wilson, J.W., Beasley, C.R., Twentyman, O.P., Howarth, R.H., and Holgate, S.T. 1990. Mucosal inflammation in asthma. Am. Rev. Respir. Dis. 142:434‐457.
   Drazen, J.M., Israel, E., and O'Byrne, P.M. 1999. Treatment of asthma with drugs modifying the leukotriene pathway. New Engl. J. Med. 340:197‐206.
   Eady, R.P. 1986. The pharmacology of nedocromil sodium. Eur. J. Respir. Dis. Suppl. 147:112‐119.
   Ellis, J.L., Undem, B.J., Kays, J.S., Ghanekar, S.V., Barthlow, H.G., and Buckner, C.K. 1993. Pharmacological examination of receptors mediating contractile responses to tachykinins in airways isolated from human, guinea pig and hamster. J. Pharmacol. Exp. Ther. 267:95‐101.
   Ellis, J.L., Hubbard, W.C., Meeker, S., and Undem, B.J. 1994. Ragweed antigen E and anti‐IgE in human central versus peripheral isolated bronchi. Am. J. Respir. Crit. Care Med. 150:717‐723.
   Empey, D.W., Laitinen, L.A., Jacobs, L., Gold, W.M., and Nadel, J.A. 1976. Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am. Rev. Respir. Dis. 113:131‐139.
   Farmer, S.G. 1997. The kallikrein‐kinin system in asthma and acute respiratory distress syndrome. In The Kinin System (S.G. Farmer, ed.) pp. 249‐263. Academic Press, New York.
   Finnerty, J.P., Twentyman, O.P., Harris, A., Palmer, J.B., and Holgate, S.T. 1991. Effect of GR32191, a potent thromboxane receptor antagonist, on exercise induced bronchoconstriction in asthma. Thorax 46:190‐192.
   Folkerts, G., Busse, W.W., Nijkamp, F.P., Sorkness, R., and Gern, J.E. 1998. Virus‐induced airway hyperresponsiveness and asthma. Am. J. Respir. Crit. Care Med. 157:1708‐1720.
   Foster, P.S., Hogan, S.P., Ramsay, A.J., Matthaei, K.I., and Young, I.G. 1996. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med. 183:195‐201.
   Gelb, A.F. and Zamel, N. 2000. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am. J. Respir. Crit. Care Med. 162:1778‐1782.
   Gibson, P.G., Zlatic, K., Scott, J., Sewell, W., Woolley, K., and Saltos, N. 1998. Chronic cough resembles asthma with IL‐5 and granulocyte‐macrophage colony‐stimulating factor gene expression in bronchoalveolar cells. J. Allergy Clin. Immunol. 101:320‐326.
   Gleich, G.J. 2000. Mechanisms of eosinophil‐associated inflammation. J. Allergy Clin. Immunol 105:651‐663.
   Gozzard, N., el‐Hashim, A., Herd, C.M., Blake, S.M., Holbrook, M., Hughes, B., Higgs, G.A., and Page, C.P. 1996. Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen‐induced airway responses in neonatally immunised rabbits. Br. J. Pharmacol. 118:1201‐1208.
   Hamelmann, E., Schwarze, J., Takeda, K., Oshiba, A., Larsen, G.L., Irvin, C.G., and Gelfand, E.W. 1997. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 156:766‐775.
   Hansen, G., Jin, S., Umetsu, D.T., and Conti, M. 2000. Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D. Proc. Natl. Acad. Sci. U.S.A. 97:6751‐6756.
   Hasday, J.D., Meltzer, S.S., Moore, W.C., Wisniewski, P., Hebel, J.R., Lanni, C., Dube, L.M., and Bleecker, E.R. 2000. Anti‐inflammatory effects of zileuton in a subpopulation of allergic asthmatics. Am. J. Respir. Crit. Care Med. 161:1229‐1236.
   el‐Hashim, A.Z., Jacques, C.A., Herd, C.M., Lee, T.H., and Page, C.P. 1997. The effect of R 15.7/HO, an anti‐CD18 antibody, on the late airway response and airway hyperresponsiveness in an allergic rabbit model. Br. J. Pharmacol. 121:671‐678.
   Havill, A.M., Van Valen, R.G., and Handley, D.A. 1990. Prevention of non‐specific airway hyperreactivity after allergen challenge in guinea‐pigs by the PAF receptor antagonist SDZ 64‐412. Br. J. Pharmacol. 99:396‐400.
   Hay, D.W.P. and Goldie, R.G. 1997. Endothelins. In Asthma (P.J. Barnes, M.M. Grunstein, A.R. Leff, and A.J. Woolcock, eds.) pp. 707‐729. Lippincott‐Raven, Philadelphia.
   Henderson, W.R. Jr, Lewis, D.B., Albert, R.K., Zhang, Y., Lamm, W.J., Chiang, G.K., Jones, F., Eriksen, P., Tien, Y.T., Jonas, M., and Chi, E.Y. 1996. The importance of leukotrienes in airway inflammation in a mouse model of asthma. J. Exp. Med. 184:1483‐1494.
   Henderson, W.R. Jr., Lu, J., Poole, K.M., Dietsch, G.N., and Chi, E.Y. 2000. Recombinant human platelet‐activating factor‐acetylhydrolase inhibits airway inflammation and hyperreactivity in mouse asthma model. J. Immunol. 164:3360‐3367.
   Henig, N.R., Aitken, M.L., Liu, M.C., Yu, A.S., and Henderson, W.R. Jr. 2000. Effect of recombinant human platelet‐activating factor‐acetylhydrolase on allergen‐induced asthmatic responses. Am. J. Respir. Crit. Care Med. 162:523‐527.
   Hisada, T., Salmon, M., Nasuhara, Y., and Chung, K.F. 1999. Cysteinyl‐leukotrienes partly mediate eotaxin‐induced bronchial hyperresponsiveness and eosinophilia in IL‐5 transgenic mice. Am. J. Respir. Crit. Care Med. 160:571‐575.
   Holgate, S.T. and Finnerty, J.P. 1989. Antihistamines in asthma. J. Allergy Clin. Immunol. 83:537‐547.
   Hoshino, M., Sim, J., Shimizu, K., Nakayama, H., and Koya, A. 1999. Effect of AA‐2414, a thromboxane A2 receptor antagonist, on airway inflammation in subjects with asthma. J. Allergy Clin. Immunol. 103:1054‐1061.
   Hughes, B., Howat, D., Lisle, H., Holbrook, M., James, T., Gozzard, N., Blease, K., Hughes, P., Kingaby, R., Warrellow, G., Alexander, R., Head, J., Boyd, E., Eaton, M., Perry, M., Wales, M., Smith, B., Owens, R., Catterall, C., Lumb, S., Russell, A., Allen, R., Merriman, M., Bloxham, D., and Higgs, G. 1996. The inhibition of antigen‐induced eosinophilia and bronchoconstriction by CDP840, a novel stereo‐selective inhibitor of phosphodiesterase type 4. Br. J. Pharmacol. 118:1183‐1191.
   Ihaku, D., Cameron, L., Suzuki, M., Molet, S., Martin, J., and Hamid, Q. 1999. Montelukast, a leukotriene receptor antagonist, inhibits the late airway response to antigen, airway eosinophilia, and IL‐5‐expressing cells in Brown Norway rats. J. Allergy Clin. Immunol. 104:1147‐1154.
   Irwin, R.S., Curley, F.J., and French, C.L. 1990. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am. Rev. Respir. Dis. 141:640‐647.
   Itoh, K., Takahashi, E., Mukaiyama, O., Satoh, Y., and Yamaguchi, T. 1996. Effects of a thromboxane synthase inhibitor (CS‐518) on the eosinophil‐dependent late asthmatic response and airway hyperresponsiveness in guinea pigs. J. Allergy Clin. Immunol. 109:79‐85.
   Karjalainen, E.M., Laitinen, A., Sue‐Chu, M., Altraja, A., Bjermer, L., and Laitinen, L.A. 2000. Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine. Am. J. Respir. Crit. Care Med. 161:2086‐2091.
   Kleeberger, S.R., Kolbe, J., Adkinson, N.F. Jr., Peters, S.P., and Spannhake, E.W. 1987. Thromboxane contributes to the immediate antigenic response of canine peripheral airways. J. Appl. Physiol. 62:1589‐1595.
   Kraneveld, A.D., van Ark, I., Van Der Linde, H.J., Fattah, D., Nijkamp, F.P., and Van Oosterhout, A.J. 1997. Antibody to very late activation antigen 4 prevents interleukin‐5‐induced airway hyperresponsiveness and eosinophil infiltration in the airways of guinea pigs. J. Allergy Clin. Immunol. 100:242‐250.
   Lalloo, U.G., Barnes, P.J., and Chung, K.F. 1996. Pathophysiology and clinical presentations of cough. J. Allergy Clin. Immunol. 98:S91‐S96.
   Lawrence, T.E., Millecchia, L.L., and Fedan, J.S. 1998. Fluticasone propionate and pentamidine isethionate reduce airway hyperreactivity, pulmonary eosinophilia and pulmonary dendritic cell response in a guinea pig model of asthma. J. Pharmacol. Exp. Ther. 284:222‐227.
   Leckie, M.J., ten Brinke, A., Khan, J., Diamant, Z., O'Connor, B.J., Walls, C.M., Mathur, A.K., Cowley, H.C., Chung, K.F., Djukanovic, R., Hansel, T.T., Holgate, S.T., Sterk, P.J., and Barnes, P.J. 2000. Effects of an interleukin‐5 blocking monoclonal antibody on eosinophils, airway hyper‐responsiveness, and the late asthmatic response. Lancet 356:2144‐2148.
   Lotvall, J., Elwood, W., Tokuyama, K., Sakamoto, T., Barnes, P.J., and Chung, K.F. 1992. A thromboxane mimetic, U‐46619, produces plasma exudation in airways of the guinea pig. J. Appl. Physiol. 72:2415‐2419.
   Mapp, C., Boschetto, P., Miotto, D., De Rosa, E., and Fabbri, L.M. 1999. Mechanisms of occupational asthma. Ann. Allergy Asthma Immunol. 83:645‐664.
   Martin, T.R., Gerard, N.P., Galli, S.J., and Drazen, J.M. 1988. Pulmonary responses to bronchoconstrictor agonists in the mouse. J. Appl. Physiol. 64:2318‐2323.
   Mathur, M., Herrmann, K., Li, X., Qin, Y., Weinstock, J., Elliott, D., Monahan, J., and Padrid, P. 1999. TRFK‐5 reverses established airway eosinophilia but not established hyperresponsiveness in a murine model of chronic asthma. Am. J. Respir. Crit. Care Med. 159:580‐587.
   Matsuoka, T., Hirata, M., Tanaka, H., Takahashi, Y., Murata, T., Kabashima, K., Sugimoto, Y., Kobayashi, T., Ushikubi, F., Aze, Y., Eguchi, N., Urade, Y., Yoshida, N., Kimura, K., Mizoguchi, A., Honda, Y., Nagai, H., and Narumiya, S. 2000. Prostaglandin D2 as a mediator of allergic asthma. Science 287:2013‐2017.
   Mauser, P.J., Pitman, A., Witt, A., Fernandez, X., Zurcher, J., Kung, T., Jones, H., Watnick, A.S., Egan, R.W., Kreutner, W., and Adams, G.K. III. 1993. Inhibitory effect of the TRFK‐5 anti‐IL‐5 antibody in a guinea pig model of asthma. Am. Rev. Respir. Dis. 148:1623‐1627.
   Mauser, P.J., Pitman, A.M., Fernandez, X., Foran, S.K., Adams, G.K. III, Kreutner, W., Egan, R.W., and Chapman, R.W. 1995. Effects of an antibody to interleukin‐5 in a monkey model of asthma. Am. J. Respir. Crit. Care Med. 152:467‐472.
   McFadden, E.R. Jr. and Gilbert, I.A. 1994. Exercise‐induced asthma. New Engl. J. Med. 330:1362‐1367.
   Milgrom, H., Fick, R.B. Jr., Su, J.Q., Reimann, J.D., Bush, R.K., Watrous, M.L., and Metzger, W.J. 1999. Treatment of allergic asthma with monoclonal anti‐IgE antibody. rhuMAb‐E25 Study Group. New Engl. J. Med. 341:1966‐1973.
   Misawa, M. and Takata, T. 1988. Effects of platelet‐activating factor on rat airways. Jpn. J. Pharmacol. 48:7‐13.
   Miyajima, I., Dombrowicz, D., Martin, T.R., Ravetch, J.V., Kinet, J.P., and Galli, S.J. 1997. Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and Fc gammaRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE‐ or IgG1‐dependent passive anaphylaxis. J. Clin. Invest. 99:901‐914.
   Molet, S., Ramos‐Barbon, D., Martin, J.G., and Hamid, Q. 1999. Adoptively transferred late allergic response is inhibited by IL‐4, but not IL‐5, antisense oligonucleotide. J. Allergy Clin. Immunol. 104:205‐214.
   Moore, R.H., Khan, A., and Dickey, B.F. 1998. Long‐acting inhaled beta2‐agonists in asthma therapy. Chest 113:1095‐1108.
   Muccitelli, R.M., Tucker, S.S., Hay, D.W., Torphy, T.J., and Wasserman, M.A. 1987. Is the guinea pig trachea a good in vitro model of human large and central airways? Comparison on leukotriene‐, methacholine‐, histamine‐ and antigen‐induced contractions. J. Pharmacol. Exp. Ther. 243:467‐473.
   Nagase, T., Ishii, S., Katayama, H., Fukuchi, Y., Ouchi, Y., and Shimizu, T. 1997. Airway responsiveness in transgenic mice overexpressing platelet‐activating factor receptor. Roles of thromboxanes and leukotrienes. Am. J. Respir. Crit. Care Med. 156:1621‐1627.
   National Heart Lung, and Blood Institute (NHLBI). 1997. National Institutes of Health (NIH) Publication No. 97‐4051. Expert Panel Report 2. Guidelines for the diagnosis and management of asthma. NHLBI, NIH, Bethesda, Md.
   Reed, C.E. 1999. The natural history of asthma in adults: The problem of irreversibility. J. Allergy Clin. Immunol. 103:539‐547.
   Robinson, D.S., Hamid, Q., Ying, S., Tsicopoulos, A., Barkans, J., Bentley, A.M., Corrigan, C., Durham, S.R., and Kay, A.B. 1992. Predominant TH2‐like bronchoalveolar T‐lymphocyte population in atopic asthma. New Engl. J. Med. 326: 298‐304
   Santing, R.E., Schraa, E.O., Wachters, A., Olymulder, C.G., Zaagsma, J., and Meurs, H. 1994. Role of histamine in allergen‐induced asthmatic reactions, bronchial hyperreactivity and inflammation in unrestrained guinea pigs. Eur. J. Pharmacol. 254:49‐57.
   Shaver, J.R., O'Connor, J.J., Pollice, M., Cho, S.K., Kane, G.C., Fish, J.E., and Peters, S.P. 1995. Pulmonary inflammation after segmental ragweed challenge in allergic asthmatic and nonasthmatic subjects. Am. J. Respir. Crit. Care Med. 152:1189‐1197.
   Shi, H., Yokoyama, A., Kohno, N., Hirasawa, Y., Kondo, K., Sakai, K., and Hiwada, K. 1998a. Effect of thromboxane A2 inhibitors on allergic pulmonary inflammation in mice. Eur. Respir. J. 11:624‐629.
   Shi, H.Z., Xiao, C.Q., Zhong, D., Qin, S.M., Liu, Y., Liang, G.R., Xu, H., Chen, Y.Q., Long, X.M., and Xie, Z.F. 1998b. Effect of inhaled interleukin‐5 on airway hyperreactivity and eosinophilia in asthmatics. Am. J. Respir. Crit. Care Med. 157:204‐209.
   Shi, H.Z., Deng, J.M., Xu, H., Nong, Z.X., Xiao, C.Q., Liu, Z.M., Qin, S.M., Jiang, H.X., Liu, G.N., and Chen, Y.Q. 1998c. Effect of inhaled interleukin‐4 on airway hyperreactivity in asthmatics. Am. J. Respir. Crit. Care Med. 157:1818‐1821.
   Skloot, G., Permutt, S., and Togias, A. 1995. Airway hyperresponsiveness in asthma: A problem of limited smooth muscle relaxation with inspiration. J. Clin. Invest. 96:2393‐2403.
   Sont, J.K., Willems, L.N., Bel, E.H., van Krieken, J.H., Vandenbroucke, J.P., and Sterk, P.J. 1999. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long‐term treatment. The AMPUL Study Group. Am. J. Respir. Crit. Care Med. 159:1043‐1051.
   Spector, S.L. (ed.) 1999. Anticholinergic agents in the upper and lower airways. Marcel Dekker, New York.
   Spence, D.P., Johnston, S.L., Calverley, P.M., Dhillon, P., Higgins, C., Ramhamadany, E., Turner, S., Winning, A., Winter, J., and Holgate, S.T. 1994. The effect of the orally active platelet‐activating factor antagonist WEB 2086 in the treatment of asthma. Am. J. Respir. Crit. Care Med. 149:1142‐1148.
   Stein, M.R. (ed.) 1999. Gastroesophageal reflux disease and airway disease. Marcel Dekker, New York.
   Stellato, C., Schweibert, L.M., and Schleimer, R.P. 1997. Mechanisms of glucocorticoid action. In Asthma (P.J. Barnes, M.M. Grunstein, A. Leff, and A.J. Woolcock, eds.) pp. 1569‐1596. Lippincott‐Raven Publishers, Philadelphia.
   Summers, J.B. and Albert, D.H. 1995. Platelet activating factor antagonists. Adv. Pharmacol. 32:67‐168.
   Torphy, T.J. 1998. Phosphodiesterase isozymes: Molecular targets for novel antiasthma agents. Am. J. Respir. Crit. Care Med. 157:351‐370.
   Turner, C.R., Andresen, C.J., Smith, W.B., and Watson, J.W. 1994a. Effects of rolipram on responses to acute and chronic antigen exposure in monkeys. Am. J. Respir. Crit. Care Med. 149:1153‐1159.
   Turner, C.R., Smith, W.B., Andresen, C.J., Swindell, A.C., and Watson, J.W. 1994b. Leukotriene D4 receptor antagonism reduces airway hyperresponsiveness in monkeys. Pulm. Pharmacol. 7:49‐58.
   Turner, C.R., Andresen, C.J., Smith, W.B., and Watson, J.W. 1996. Characterization of a primate model of asthma using anti‐allergy/anti‐asthma agents. Inflamm. Res. 45:239‐245.
   Undem, B.J., Buckner, C.K., Harley, P., and Graziano, F.M. 1985. Smooth muscle contraction and release of histamine and slow‐reacting substance of anaphylaxis in pulmonary tissues isolated from guinea pigs passively sensitized with IgG1 or IgE antibodies. Am. Rev. Respir. Dis. 131:260‐266.
   Underwood, D.C., Kotzer, C.J., Bochnowicz, S., Osborn, R.R., Luttmann, M.A., Hay, D.W., and Torphy, T.J. 1994. Comparison of phosphodiesterase III, IV and dual III/IV inhibitors on bronchospasm and pulmonary eosinophil influx in guinea pigs. J. Pharmacol. Exp. Ther. 270:250‐259.
   Underwood, D.C., Osborn, R.R., Newsholme, S.J., Torphy, T.J., and Hay, D.W. 1996. Persistent airway eosinophilia after leukotriene (LT) D4 administration in the guinea pig: Modulation by the LTD4 receptor antagonist, pranlukast, or an interleukin‐5 monoclonal antibody. Am. J. Respir. Crit. Care Med. 154:850‐857.
   Van Koppen, C.J., Rodrigues De Miranda, J.F., Beld, A.J., Van Ginneken, C.A., Lammers, J.W., and Van Herwaarden, C.L. 1988. Muscarinic receptor sensitivity in airway smooth muscle of patients with obstructive airway disease. Arch. Int. Pharmacodyn. Ther. 295:238‐244.
   Viel, L. 1997. Small airway disease as a vanguard for chronic obstructive pulmonary disease. Vet. Clin. North Am. Equine Pract. 13:549‐560.
   Watanabe, A. and Hayashi, H. 1990. Allergen‐induced biphasic bronchoconstriction in rats. Int. Arch. Allergy Appl. Immunol. 93:26‐34.
   West, J.B. 2000. Respiratory Physiology—The Essentials. Lippincott Williams & Wilkins, Philadelphia.
   Xu, L., Olivenstein, R., Martin, J.G., and Powell, W.S. 2000. Inhaled budesonide inhibits OVA‐induced airway narrowing, inflammation, and cys‐LT synthesis in BN rats. J. Appl. Physiol. 89:1852‐1858.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library