Background: Serum-derived hyaluronan (HA)-associated proteins (SHAPs), the heavy chains of inter-α-trypsin inhibitor, covalently bind to HA to form the SHAP-HA complex. The SHAP-HA complex is involved in the pathophysiology of inflammatory diseases, including rheumatoid arthritis. We investigated whether this complex is also involved in airway allergy. Methods: SHAP-HA-deficient (bikunin knockout, KO) mice and wild-type (WT) mice were immunized twice by intraperitoneal injection of ovalbumin (OVA) and exposed to aerosol OVA for 30 min each day for 2 weeks. Twenty-four hours after the final OVA challenge, airway responsiveness to inhaled methacholine (MCh) was measured, and analysis of bronchoalveolar lavage fluid (BALF) and lung histological studies were done. Results: Compared to WT mice, KO mice showed higher airway hyperresponsiveness to inhaled MCh and higher late-phase responses to OVA whereas the early-phase responses were similar. Cell differentials of BALF showed an increased number of macrophages and neutrophils in KO mice. Furthermore, decreased concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1) were found in BALF from KO mice whereas the levels of Th1 and Th2 cytokines were not different from WT mice. Immunochemical study of the lung tissues revealed stronger staining of sTNFR1 in KO than in WT mice. Conclusions: Our results suggest that in this murine asthma model, the SHAP-HA complex has an inhibitory role in the development of airway hyperresponsiveness and allergic airway inflammation which may be attributed, at least in part, to negative feedback mechanisms exerted by sTNFR1, the shedding of which from the cell surface might also be promoted by the SHAP-HA complex.

Keywords:
Serum-derived hyaluronan-associated proteins, Hyaluronan, Soluble tumor necrosis factor receptor-1, Interleukin-12p40, Asthma, Airway hyperresponsiveness
1.
Elias JA, Zhu Z, Chupp G, Homer RJ: Airway remodeling in asthma. J Clin Invest 1999;104:1001–1006.
2.
Fahy JV, Corry DB, Boushey HA: Airway inflammation and remodeling in asthma. Curr Opin Pulm Med 2000;6:15–20.
3.
Jeffery PK: Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 2001;164:S28–S38.
4.
Umetsu DT, McIntire JJ, Akbari O, Macaubas C, DeKruyff RH: Asthma: An epidemic of dysregulated immunity. Nat Immunol 2002;3:715–720.
5.
Hirst SJ, Twort CH, Lee TH: Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. Am J Respir Cell Mol Biol 2000;23:335–344.
6.
Sahu S, Lynn WS: Hyaluronic acid in the pulmonary secretions of patients with asthma. Biochem J 1978;173:565–568.
7.
Wilkinson TS, Potter-Perigo S, Tsoi C, Altman LC, Wight TN: Pro- and anti-inflammatory factors cooperate to control hyaluronan synthesis in lung fibroblasts. Am J Respir Cell Mol Biol 2004;31:92–99.
8.
Lauer ME, Mukhopadhyay D, Fulop C, de la Motte CA, Majors AK, Hascall VC: Primary murine airway smooth muscle cells exposed to poly(I,C) or tunicamycin synthesize a leukocyte-adhesive hyaluronan matrix. J Biol Chem 2008;284:5299–5312.
9.
Jiang D, Liang J, Noble PW: Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol 2007;23:435–461.
10.
Akatsuka M, Yamamoto Y, Tobetto K, Yasui T, Ando T: Suppressive effects of hyaluronic acid on elastase release from rat peritoneal leucocytes. J Pharm Pharmacol 1993;45:110–114.
11.
Kunz LI, van Rensen EL, Sterk PJ: Inhaled hyaluronic acid against exercise-induced bronchoconstriction in asthma. Pulm Pharmacol Ther 2006;19:286–291.
12.
Petrigni G, Allegra L: Aerosolised hyaluronic acid prevents exercise-induced bronchoconstriction, suggesting novel hypotheses on the correction of matrix defects in asthma. Pulm Pharmacol Ther 2006;19:166–171.
13.
Bousquet J, Chanez P, Lacoste JY, Enander I, Venge P, Peterson C, Ahlstedt S, Michel FB, Godard P: Indirect evidence of bronchial inflammation assessed by titration of inflammatory mediators in BAL fluid of patients with asthma. J Allergy Clin Immunol 1991;88:649–660.
14.
Teder P, Vandivier RW, Jiang D, Liang J, Cohn L, Pure E, Henson PM, Noble PW: Resolution of lung inflammation by CD44. Science 2002;296:155–158.
15.
Yoneda M, Suzuki S, Kimata K: Hyaluronic acid associated with the surfaces of cultured fibroblasts is linked to a serum-derived 85-kDa protein. J Biol Chem 1990;265:5247–5257.
16.
Huang L, Yoneda M, Kimata K: A serum-derived hyaluronan-associated protein (SHAP) is the heavy chain of the inter α-trypsin inhibitor. J Biol Chem 1993;268:26725–26730.
17.
Zhao M, Yoneda M, Ohashi Y, Kurono S, Iwata H, Ohnuki Y, Kimata K: Evidence for the covalent binding of SHAP, heavy chains of inter-α-trypsin inhibitor, to hyaluronan. J Biol Chem 1995;270:26657–26663.
18.
Zhuo L, Yoneda M, Zhao M, Yingsung W, Yoshida N, Kitagawa Y, Kawamura K, Suzuki T, Kimata K: Defect in SHAP-hyaluronan complex causes severe female infertility. A study by inactivation of the bikunin gene in mice. J Biol Chem 2001;276:7693–7696.
19.
de la Motte CA, Hascall VC, Drazba J, Bandyopadhyay SK, Strong SA: Mononuclear leukocytes bind to specific hyaluronan structures on colon mucosal smooth muscle cells treated with polyinosinic acid:polycytidylic acid: inter-α-trypsin inhibitor is crucial to structure and function. Am J Pathol 2003;163:121–133.
20.
Zhuo L, Kanamori A, Kannagi R, Itano N, Wu J, Hamaguchi M, Ishiguro N, Kimata K: SHAP potentiates the CD44-mediated leukocyte adhesion to the hyaluronan substratum. J Biol Chem 2006;281:20303–20314.
21.
Garantziotis S, Zudaire E, Trempus CS, Hollingsworth JW, Jiang D, Lancaster LH, Richardson E, Zhuo L, Cuttitta F, Brown KK, Noble PW, Kimata K, Schwartz DA: Serum inter-α-trypsin inhibitor and matrix hyaluronan promote angiogenesis in fibrotic lung injury. Am J Respir Crit Care Med 2008;178:939–947.
22.
Hamelmann E, Schwarze J, Takeda K, Oshiba A, Larsen GL, Irvin CG, Gelfand EW: Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am J Respir Crit Care Med 1997;156:766–775.
23.
Lomask M: Further exploration of the Penh parameter. Exp Toxicol Pathol 2006;57 (suppl 2):13–20.
24.
Keramidaris E, Merson TD, Steeber DA, Tedder TF, Tang ML: L-selectin and intercellular adhesion molecule 1 mediate lymphocyte migration to the inflamed airway/lung during an allergic inflammatory response in an animal model of asthma. J Allergy Clin Immunol 2001;107:734–738.
25.
Kida D, Yoneda M, Miyaura S, Ishimaru T, Yoshida Y, Ito T, Ishiguro N, Iwata H, Kimata K: The SHAP-HA complex in sera from patients with rheumatoid arthritis and osteoarthritis. J Rheumatol 1999;26:1230–1238.
26.
Dohi M, Tsukamoto S, Nagahori T, Shinagawa K, Saitoh K, Tanaka Y, Kobayashi S, Tanaka R, To Y, Yamamoto K: Noninvasive system for evaluating the allergen-specific airway response in a murine model of asthma. Lab Invest 1999;79:1559–1571.
27.
Lundblad LK, Irvin CG, Adler A, Bates JH: A reevaluation of the validity of unrestrained plethysmography in mice. J Appl Physiol 2002;93:1198–1207.
28.
Adler A, Cieslewicz G, Irvin CG: Unrestrained plethysmography is an unreliable measure of airway responsiveness in BALB/c and C57BL/6 mice. J Appl Physiol 2004;97:286–292.
29.
Zosky GR, Larcombe AN, White OJ, Burchell JT, Janosi TZ, Hantos Z, Holt PG, Sly PD, Turner DJ: Ovalbumin-sensitized mice are good models for airway hyperresponsiveness but not acute physiological responses to allergen inhalation. Clin Exp Allergy 2008;38:829–838.
30.
Facincone S, De Siqueira AL, Jancar S, Russo M, Barbuto JA, Mariano M: A novel murine model of late-phase reaction of immediate hypersensitivity. Mediators Inflamm 1997;6:127–133.
31.
Stern R, Asari AA, Sugahara KN: Hyaluronan fragments: an information-rich system. Eur J Cell Biol 2006;85:699–715.
32.
Savani RC, Hou G, Liu P, Wang C, Simons E, Grimm PC, Stern R, Greenberg AH, DeLisser HM, Khalil N: A role for hyaluronan in macrophage accumulation and collagen deposition after bleomycin-induced lung injury. Am J Respir Cell Mol Biol 2000;23:475–484.
33.
Ohkawara Y, Tamura G, Iwasaki T, Tanaka A, Kikuchi T, Shirato K: Activation and transforming growth factor-β production in eosinophils by hyaluronan. Am J Respir Cell Mol Biol 2000;23:444–451.
34.
Hutadilok N, Ghosh P, Brooks PM: Binding of haptoglobin, inter-α-trypsin inhibitor, and α1-proteinase inhibitor to synovial fluid hyaluronate and the influence of these proteins on its degradation by oxygen-derived free radicals. Ann Rheum Dis 1988;47:377–385.
35.
Ling P, Gately MK, Gubler U, Stern AS, Lin P, Hollfelder K, Su C, Pan YC, Hakimi J: Human IL-12 p40 homodimer binds to the IL-12 receptor but does not mediate biologic activity. J Immunol 1995;154:116–127.
36.
Gately MK, Carvajal DM, Connaughton SE, Gillessen S, Warrier RR, Kolinsky KD, Wilkinson VL, Dwyer CM, Higgins GF Jr, Podlaski FJ, Faherty DA, Familletti PC, Stern AS, Presky DH: Interleukin-12 antagonist activity of mouse interleukin-12 p40 homodimer in vitro and in vivo. Ann NY Acad Sci 1996;795:1–12.
37.
Cooper AM, Khader SA: Il-12p40: an inherently agonistic cytokine. Trends Immunol 2007;28:33–38.
38.
Mattner F, Fischer S, Guckes S, Jin S, Kaulen H, Schmitt E, Rude E, Germann T: The interleukin-12 subunit p40 specifically inhibits effects of the interleukin-12 heterodimer. Eur J Immunol 1993;23:2202–2208.
39.
Holgate ST, Polosa R: Treatment strategies for allergy and asthma. Nat Rev Immunol 2008;8:218–230.
40.
Thomas PS, Yates DH, Barnes PJ: Tumor necrosis factor-α increases airway responsiveness and sputum neutrophilia in normal human subjects. Am J Respir Crit Care Med 1995;152:76–80.
41.
Choi IW, Sun K, Kim YS, Ko HM, Im SY, Kim JH, You HJ, Lee YC, Lee JH, Park YM, Lee HK: TNF-α induces the late-phase airway hyperresponsiveness and airway inflammation through cytosolic phospholipase A2 activation. J Allergy Clin Immunol 2005;116:537–543.
42.
Brightling C, Berry M, Amrani Y: Targeting TNF-α: a novel therapeutic approach for asthma. J Allergy Clin Immunol 2008;121:5–10; quiz 11–12.
43.
Hutchison S, Choo-Kang BS, Bundick RV, Leishman AJ, Brewer JM, McInnes IB, Garside P: Tumour necrosis factor-α blockade suppresses murine allergic airways inflammation. Clin Exp Immunol 2008;151:114–122.
44.
Wong M, Ziring D, Korin Y, Desai S, Kim S, Lin J, Gjertson D, Braun J, Reed E, Singh RR: TNF-α blockade in human diseases: mechanisms and future directions. Clin Immunol 2008;126:121–136.
45.
Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W, Beckett P, Al Ali M, Chauhan A, Wilson SJ, Reynolds A, Davies DE, Holgate ST: Tumour necrosis factor (TNF-α) as a novel therapeutic target in symptomatic corticosteroid-dependent asthma. Thorax 2005;60:1012–1018.
46.
Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, Bradding P, Brightling CE, Wardlaw AJ, Pavord ID: Evidence of a role of tumor necrosis factor-α in refractory asthma. N Engl J Med 2006;354:697–708.
47.
Klinkhoff A: Biological agents for rheumatoid arthritis: targeting both physical function and structural damage. Drugs 2004;64:1267–1283.
48.
Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST: The role of a soluble TNF α receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double-blind, randomised, placebo-controlled trial. Thorax 2008;63:584–591.
49.
Amrani Y, Martinet N, Bronner C: Potentiation by tumour necrosis factor-α of calcium signals induced by bradykinin and carbachol in human tracheal smooth muscle cells. Br J Pharmacol 1995;114:4–5.
50.
Kang BN, Deshpande DA, Tirumurugaan KG, Panettieri RA, Walseth TF, Kannan MS: Adenoviral mediated anti-sense CD38 attenuates TNF-α-induced changes in calcium homeostasis of human airway smooth muscle cells. Can J Physiol Pharmacol 2005;83:799–804.
51.
Sugiki M, Sumi H, Maruyama M, Yoshida E, Mihara H: Clearance and distribution of acid-stable trypsin inhibitor (ASTI). Enzyme 1989;42:31–38.
52.
Jonsson-Berling BM, Ohlsson K: Distribution and elimination of intravenously injected urinary trypsin inhibitor. Scand J Clin Lab Invest 1991;51:549–557.
© 2010 S. Karger AG, Basel
2010
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.