Airway wall remodeling: Friend or foe?

Journal of Applied Physiology

Volumn 95, Issue 1, 2003, Pages 426-434

  McParland, Brent E ^a   Macklem, Peter T ^b   Paré, Peter D ^a,c  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^b MCGILL UNIVERSITY   (Canada)

^c ST PAUL S HOSPITAL   (Canada)

Author keywords

Asthma; Pathophysiology; Smooth muscle

Indexed keywords

ACETYLCHOLINE; CARBACHOL; HISTAMINE; ISOPRENALINE; LEUKOTRIENE C4; METHACHOLINE;

AIRWAY; ASTHMA; BRONCHUS; BRONCHUS HYPERREACTIVITY; ELASTICITY; HUMAN; INFLAMMATION; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; RESPIRATORY EPITHELIUM; REVIEW; SMOOTH MUSCLE CONTRACTION;

EID: 0038308638     PISSN: 87507587     EISSN: None     Source Type: Journal    
DOI: 10.1152/japplphysiol.00159.2003     Document Type: Review

References (120)

1. Armour CL, Diment LM, and Black JL. Relationship between smooth muscle volume and contractile response in airway tissue. Isometric versus isotonic measurement. J Pharmacol Exp Ther 245: 687-691, 1988.
2. Bai TR. Abnormalities in airway smooth muscle in fatal asthma. Am Rev Respir Dis 141: 552-557, 1990.
3. Bai TR. Abnormalities in airway smooth muscle in fatal asthma. A comparison between trachea and bronchus. Am Rev Respir Dis 143: 441-443, 1991.
4. Bai TR, Cooper J, Koelmeyer T, Pare PD, and Weir TD. The effect of age and duration of disease on airway structure in fatal asthma. Am J Respir Crit Care Med 162: 663-669, 2000.
5. Beasley R, Roche WR, Roberts JA, and Holgate ST. Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 139: 806-817, 1989.
6. Boulet LP, Laviolette M, Turcotte H, Cartier A, Dugas M, Malo JL, and Boutet M. Bronchial subepithelial fibrosis correlates with airway responsiveness to methacholine. Chest 112: 45-52, 1997.
7. Bousquet J, Lacoste JY, Chanez P, Vic P, Godard P, and Michel FB. Bronchial elastic fibers in normal subjects and asthmatic patients. Am J Respir Crit Care Med 153: 1648-1654, 1996.
8. Bramley AM, Roberts CR, and Schellenberg RR. Collagenase increases shortening of human bronchial smooth muscle in vitro. Am J Respir Crit Care Med 152: 1513-1517, 1995.
9. Bramley AM, Roberts CR, and Schellenberg RR. Hyaluronidase increases human bronchial smooth muscle shortening in vitro (Abstract). Am J Respir Crit Care Med 157: A518, 1998.
10. Bramley AM, Thomson RJ, Roberts CR, and Schellenberg RR. Hypothesis: excessive bronchoconstriction in asthma is due to decreased airway elastance. Eur Respir J 7: 337-341, 1994.
11. Brewster CE, Howarth PH, Djukanovic R, Wilson J, Holgate ST, and Roche WR. Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 3: 507-511, 1990.
12. Brown RH and Mitzner W. The myth of maximal airway responsiveness in vivo. J Appl Physiol 85: 2012-2017, 1998.
13. Brown RH, Scichilone N, Mudge B, Diemer FB, Permutt S, and Togias A. High-resolution computed tomographic evaluation of airway distensibility and the effects of lung inflation on airway caliber in healthy subjects and individuals with asthma. Am J Respir Crit Care Med 163: 994-1001, 2001.
14. Burns CB, Taylor WR, and Ingram RH Jr. Effects of deep inhalation in asthma: relative airway and parenchymal hysteresis. J Appl Physiol 59: 1590-1596, 1985.
15. Carroll N, Elliot J, Morton A, and James A. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 147: 405-410, 1993.
16. Carroll NG, Cooke C, and James AL. Bronchial blood vessel dimensions in asthma. Am J Respir Crit Care Med 155: 689-695, 1997.
17. Carroll NG, Perry S, Karkhanis A, Harji S, Butt J, James AL, and Green FH. The airway longitudinal elastic fiber network and mucosal folding in patients with asthma. Am J Respir Crit Care Med 161: 244-248, 2000.
18. Cerrina J, Labat C, Haye-Legrande I, Raffestin B, Benveniste J, and Brink C. Human isolated bronchial muscle preparations from asthmatic patients: effects of indomethacin and contractile agonists. Prostaglandins 37: 457-469, 1989.
19. Cerrina J, Le Roy Ladurie M, Labat C, Raffestin B, Bayol A, and Brink C. Comparison of human bronchial muscle responses to histamine in vivo with histamine and isoproterenol agonists in vitro. Am Rev Respir Dis 134: 57-61, 1986.
20. Dawson SV and Elliott EA. Wave-speed limitation on expiratory flow - a unifying concept. J Appl Physiol 43: 498-515, 1977.
21. De Jongste JC, Mons H, Bonta IL, and Kerrebijn KF. In vitro responses of airways from an asthmatic patient. Eur J Respir Dis 71: 23-29, 1987.
22. De Pee S, Timmers MC, Hermans J, Duiverman EJ, and Sterk PJ. Comparison of maximal airway narrowing to methacholine between children and adults. Eur Respir J 4: 421-428, 1991.
23. Ding DJ, Martin JG, and Macklem PT. Effects of lung volume on maximal methacholine-induced bronchoconstriction in normal humans. J Appl Physiol 62: 1324-1330, 1987.
24. Djukanovic R, Lai CK, Wilson JW, Britten KM, Wilson SJ, Roche WR, Howarth PH, and Holgate ST. Bronchial mucosal manifestations of atopy: a comparison of markers of inflammation between atopic asthmatics, atopic nonasthmatics and healthy controls. Eur Respir J 5: 538-544, 1992.
25. Dunnill M, Massarella G, and Anderson J. A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis, and in emphysema. Thorax 24: 176-179, 1969.
26. Ebina M, Takahashi T, Chiba T, and Motomiya M. Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. Am Rev Respir Dis 148: 720-726, 1993.
27. Ebina M, Yaegashi H, Chiba R, Takahashi T, Motomiya M, and Tanemura M. Hyperreactive site in the airway tree of asthmatic patients revealed by thickening of bronchial muscles. A morphometric study. Am Rev Respir Dis 141: 1327-1332, 1990.
28. Finucane KE and Colebatch HJ. Elastic behavior of the lung in patients with airway obstruction. J Appl Physiol 26: 330-338, 1969.
29. Fish JE, Peterman VI, and Cugell DW. Effect of deep inspiration on airway conductance in subjects with allergic rhinitis and allergic asthma. J Allergy Clin Immunol 60: 41-46, 1977.
30. Fredberg JJ. Frozen objects: small airways, big breaths, and asthma. J Allergy Clin Immunol 106: 615-624, 2000.
31. Fredberg JJ, Inouye D, Miller B, Nathan M, Jafari S, Raboudi SH, Butler JP, and Shore SA. Airway smooth muscle, tidal stretches, and dynamically determined contractile states. Am J Respir Crit Care Med 156: 1752-1759, 1997.
32. Fredberg JJ, Jones KA, Nathan M, Raboudi S, Prakash YS, Shore SA, Butler JP, and Sieck GC. Friction in airway smooth muscle: mechanism, latch, and implications in asthma. J Appl Physiol 81: 2703-2712, 1996.
33. Froeb HF and Mead J. Relative hysteresis of the dead space and lung in vivo. J Appl Physiol 25: 244-248, 1968.
34. Gabbrielli S, Di Lollo S, Stanflin N, and Romagnoli P. Myofibroblast and elastic and collagen fiber hyperplasia in the bronchial mucosa: a possible basis for the progressive irreversibility of airway obstruction in chronic asthma. Pathologica 86: 157-160, 1994.
35. Gelb AF, Licuanan J, Shinar CM, and Zamel N. Unsuspected loss of lung elastic recoil in chronic persistent asthma. Chest 121: 715-721, 2002.
36. Gillis JM, Cao ML, and Godfraind-De Becker A. Density of myosin filaments in the rat anococcygeus muscle, at rest and in contraction. II. J Muscle Res Cell Motil 9: 18-29, 1988.
37. Gold WM, Kaufman HS, and Nadel JA. Elastic recoil of the lungs in chronic asthmatic patients before and after therapy. J Appl Physiol 23: 433-438, 1967.
38. Goldie RG, Spina D, Henry PJ, Lulich KM, and Paterson JW. In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, β-adrenoceptor agonists and theophylline. Br J Clin Pharmacol 22: 669-676, 1986.
39. Gunst SJ, Stropp JQ, and Service J. Mechanical modulation of pressure-volume characteristics of contracted canine airways in vitro. J Appl Physiol 68: 2223-2229, 1990.
40. Gunst SJ, Warner DO, Wilson TA, and Hyatt RE. Parenchymal interdependence and airway response to methacholine in excised dog lobes. J Appl Physiol 65: 2490-2497, 1988.
41. Heard BE and Hossain S. Hyperplasia of bronchial muscle in asthma. J Pathol 110: 319-331, 1973.
42. Herrera AM, Kuo KH, and Seow CY. Influence of calcium on myosin thick filament formation in intact airway smooth muscle. Am J Physiol Cell Physiol 282: C310-C316, 2002.
43. Hillman DR and Finucane KE. The effect of hyperinflation on lung elasticity in healthy subjects. Respir Physiol 54: 295-305, 1983.
44. Hogg JC. The pathology of asthma. Clin Chest Med 5: 567-571, 1984.
45. Holgate ST. Inflammatory and structural changes in the airways of patients with asthma. Respir Med 94: S3-6, 2000.
46. Hoshino M, Takahashi M, and Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. J Allergy Clin Immunol 107: 295-301, 2001.
47. Hossain S. Quantitative measurement of bronchial muscle in men with asthma. Am Rev Respir Dis 107: 99-109, 1973.
48. Huang J, Olivenstein R, Taha R, Hamid Q, and Ludwig M. Enhanced proteoglycan deposition in the airway wall of atopic asthmatics. Am J Respir Crit Care Med 160: 725-729, 1999.
49. Huber H and Koessler K. The pathology of bronchial asthma. Arch Intern Med 30: 689-760, 1922.
50. Irvin CG, Pak J, and Martin RJ. Airway-parenchyma uncoupling in nocturnal asthma. Am J Respir Crit Care Med 161: 50-56, 2000.
51. Jackson AC, Rassulo J, Marquina J, and Celli B. Influence of deep inspiration on methacholine induced bronchoconstriction (Abstract). Am J Respir Crit Care Med 159: A468, 1999.
52. James AL, Hogg JC, Dunn LA, and Pare PD. The use of the internal perimeter to compare airway size and to calculate smooth muscle shortening. Am Rev Respir Dis 138: 136-139, 1988.
53. James AL, Pare PD, and Hogg JC. The mechanics of airway narrowing in asthma. Am Rev Respir Dis 139: 242-246, 1989.
54. Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, and Kay AB. Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 140: 1745-1753, 1989.
55. Jiang H, Rao K, Halayko AJ, Kepron W, and Stephens NL. Bronchial smooth muscle mechanics of a canine model of allergic airway hyperresponsiveness. J Appl Physiol 72: 39-45, 1992.
56. Johnson PR, Black JL, Carlin S, Ge Q, and Underwood PA. The production of extracellular matrix proteins by human passively sensitized airway smooth-muscle cells in culture: the effect of beclomethasone. Am J Respir Crit Care Med 162: 2145-2151, 2000.
57. King GG, Eberl S, Salome CM, Young IH, and Woolcock AJ. Differences in airway closure between normal and asthmatic subjects measured with single-photon emission computed tomography and technegas. Am J Respir Crit Care Med 158: 1900-1906, 1998.
58. Kuo KH, Wang L, Pare PD, Ford LE, and Seow CY. Myosin thick filament lability induced by mechanical strain in airway smooth muscle. J Appl Physiol 90: 1811-1816, 2001.
59. Kuwano K, Bosken CH, Pare PD, Bai TR, Wiggs BR, and Hogg JC. Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 148: 1220-1225, 1993.
60. Laitinen LA, Heino M, Laitinen A, Kava T, and Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 131: 599-606, 1985.
61. Lambert RK. Role of bronchial basement membrane in airway collapse. J Appl Physiol 71: 666-673, 1991.
62. Lambert RK and Pare PD. Lung parenchymal shear modulus, airway wall remodeling, and bronchial hyperresponsiveness. J Appl Physiol 83: 140-147, 1997.
63. Lambert RK, Wiggs BR, Kuwano K, Hogg JC, and Pare PD. Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol 74: 2771-2781, 1993.
64. Laprise C, Laviolette M, Boutet M, and Boulet LP. Asymptomatic airway hyperresponsiveness: relationships with airway inflammation and remodelling. Eur Respir J 14: 63-73, 1999.
65. Li X and Wilson JW. Increased vascularity of the bronchial mucosa in mild asthma. Am J Respir Crit Care Med 156: 229-233, 1997.
66. Lim TK, Pride NB, and Ingram RH Jr. Effects of volume history during spontaneous and acutely induced air-flow obstruction in asthma. Am Rev Respir Dis 135: 591-596, 1987.
67. Macklem PT. Bronchial hyporesponsiveness. Chest 91: 189S-191S, 1987.
68. Macklem PT. A hypothesis linking bronchial hyperreactivity and airway inflammation: implications for therapy. Ann Allergy Asthma Immunol 64: 113-116, 1990.
69. Macklem PT. A theoretical analysis of the effect of airway smooth muscle load on airway narrowing. Am J Respir Crit Care Med 153: 83-89, 1996.
70. Mandelbrot BB. A multifractal walk down Wall Street. Sci Am 280: 70-73, 1999.
71. Mauad T, Xavier AC, Saldiva PH, and Dolhnikoff M. Elastosis and fragmentation of fibers of the elastic system in fatal asthma. Am J Respir Crit Care Med 160: 968-975, 1999.
72. McParland BE, Johnson PR, Armour C, and Black JL. Human bronchial internal perimeter is not a constant (Abstract). Am J Respir Crit Care Med 163: A415, 2001.
73. McParland BE, Pare PD, and Seow CY. Plasticity is not just a phenomenon of tracheal smooth muscle. Am J Respir Crit Care Med In press.
74. McParland BE, Wiggs BR, Johnson PR, Armour C, and Black JL. Airway mucosal folding: is it REALLY a load to smooth muscle shortening (Abstract)? Am J Respir Crit Care Med 157: A517, 1998.
75. Mead J, Takishima T, and Leith D. Stress distribution in lungs: a model of pulmonary elasticity. J Appl Physiol 28: 596-608, 1970.
76. Meiss RA. Influence of intercellular tissue connections on airway muscle mechanics. J Appl Physiol 86: 5-15, 1999.
77. Milanese M, Crimi E, Scordamaglia A, Riccio A, Pellegrino R, Canonica GW, and Brusasco V. On the functional consequences of bronchial basement membrane thickening. J Appl Physiol 91: 1035-1040, 2001.
78. Momose K, Otsuka H, Higashikawa S, and Gomi Y. Studies on isolated smooth muscle cells. VII. Response to agonists and the contraction velocity of taenia coli of guinea pig and the single smooth muscle cells. J Pharmacobio-Dyn 4: 670-676, 1981.
79. Moore BJ, Hilliam CC, Verburgt LM, Wiggs BR, Vedal S, and Pare PD. Shape and position of the complete dose-response curve for inhaled methacholine in normal subjects. Am J Respir Crit Care Med 154: 642-648, 1996.
80. Moore BJ, Verburgt LM, King GG, and Pare PD. The effect of deep inspiration on methacholine dose-response curves in normal subjects. Am J Respir Crit Care Med 156: 1278-1281, 1997.
81. Moreno RH, Hogg JC, and Pare PD. Mechanics of airway narrowing. Am Rev Respir Dis 133: 1171-1180, 1986.
82. Olivieri D and Foresi A. Correlation between cell content of bronchoalveolar lavage (BAL) and histologic findings in asthma. Respiration 59, Suppl 1: 3-5, 1992.
83. Omari TI, Sparrow MP, and Mitchell HW. Responsiveness of human isolated bronchial segments and its relationship to epithelial loss. J Clin Pharmacol 35: 357-365, 1993.
84. Ordonez CL, Khashayar R, Wong HH, Ferrando R, Wu R, Hyde DM, Hotchkiss JA, Zhang Y, Novikov A, Dolganov G, and Fahy JV. Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am J Respir Crit Care Med 163: 517-523, 2001.
85. Orsida BE, Li X, Hickey B, Thien F, Wilson JW, and Walters EH. Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax 54: 289-295, 1999.
86. Orsida BE, Ward C, Li X, Bish R, Wilson JW, Thien F, and Walters EH. Effect of a long-acting β2-agonist over three months on airway wall vascular remodeling in asthma. Am J Respir Crit Care Med 164: 117-121, 2001.
87. Palmans E, Kips JC, and Pauwels RA. Prolonged allergen exposure induces structural airway changes in sensitized rats. Am J Respir Crit Care Med 161: 627-635, 2000.
88. Pare PD and Bai TR. The consequences of chronic allergic inflammation. Thorax 50: 328-332, 1995.
89. Pare PD, Wiggs BR, James A, Hogg JC, and Bosken C. The comparative mechanics and morphology of airways in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 143: 1189-1193, 1991.
90. Parham WM, Shepard RH, Norman PS, and Fish JE. Analysis of time course and magnitude of lung inflation effects on airway tone: relation to airway reactivity. Am Rev Respir Dis 128: 240-245, 1983.
91. Pedersen OF, Brackel HJ, Bogaard JM, and Kerrebijn KF. Wave-speed-determined flow limitation at peak flow in normal and asthmatic subjects. J Appl Physiol 83: 1721-1732, 1997.
92. Peress L, Sybrecht G, and Macklem PT. The mechanism of increase in total lung capacity during acute asthma. Am J Med 61: 165-169, 1976.
93. Persson CG, Erjefalt JS, Erjefalt I, Korsgren MC, Nilsson MC, and Sundler F. Epithelial shedding - restitution as a causative process in airway inflammation. Clin Exp Allergy 26: 746-755, 1996.
94. Pliss LB, Ingenito EP, and Ingram RH Jr. Responsiveness, inflammation, and effects of deep breaths on obstruction in mild asthma. J Appl Physiol 66: 2298-2304, 1989.
95. Pratusevich VR, Seow CY, and Ford LE. Plasticity in canine airway smooth muscle. J Gen Physiol 105: 73-94, 1995.
96. Qi D, Mitchell RW, Burdyga T, Ford LE, Kuo KH, and Seow CY. Myosin light chain phosphorylation facilitates in vivo myosin filament reassembly after mechanical perturbation. Am J Physiol Cell Physiol 282: C1298-C1305, 2002.
97. Que CL, Kenyon CM, Olivenstein R, Macklem PT, and Maksym GN. Homeokinesis and short-term variability of human airway caliber. J Appl Physiol 91: 1131-1141, 2001.
98. Roberts JA, Raeburn D, Rodger IW, and Thomson NC. Comparison of in vivo airway responsiveness and in vitro smooth muscle sensitivity to methacholine in man. Thorax 39: 837-843, 1984.
99. Roche WR, Beasley R, Williams JH, and Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1: 520-524, 1989.
100. Saetta M, Di Stefano A, Rosina C, Thiene G, and Fabbri LM. Quantitative structural analysis of peripheral airways and arteries in sudden fatal asthma. Am Rev Respir Dis 143: 138-143, 1991.
101. Schellenberg RR and Foster A. In vitro responses of human asthmatic airway and pulmonary vascular smooth muscle. Int Arch Allergy Appl Immunol 75: 237-241, 1984.
102. Shen X, Wu MF, Tepper RS, and Gunst SJ. Mechanisms for the mechanical response of airway smooth muscle to length oscillation. J Appl Physiol 83: 731-738, 1997.
103. Skloot G, Permutt S, and Togias A. Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration. J Clin Invest 96: 2393-2403, 1995.
104. Sobonya RE. Quantitative structural alterations in long-standing allergic asthma. Am Rev Respir Dis 130: 289-292, 1984.
105. Solway J and Fredberg JJ. Perhaps airway smooth muscle dysfunction contributes to asthmatic bronchial hyperresponsiveness after all. Am J Respir Cell Mol Biol 17: 144-146, 1997.
106. Sterk PJ, Daniel EE, Zamel N, and Hargreave FE. Limited bronchoconstriction to methacholine using partial flow-volume curves in nonasthmatic subjects. Am Rev Respir Dis 132: 272-277, 1985.
107. Takizawa T and Thurlbeck WM. Muscle and mucous gland size in the major bronchi of patients with chronic bronchitis, asthma, and asthmatic bronchitis. Am Rev Respir Dis 104: 331-336, 1971.
108. Thomson RJ, Bramley AM, and Schellenberg RR. Airway muscle stereology: implications for increased shortening in asthma. Am J Respir Crit Care Med 154: 749-757, 1996.
109. Vanacker NJ, Palmans E, Pauwels RA, and Kips JC. Fluticasone inhibits the progression of allergen-induced structural airway changes. Clin Exp Allergy 32: 914-920, 2002.
110. Wang L, Pare PD, and Seow CY. Changes in force-velocity properties of trachealis due to oscillatory strains. J Appl Physiol 92: 1865-1872, 2002.
111. Wang L, Pare PD, and Seow CY. Effects of length oscillation on the subsequent force development in swine tracheal smooth muscle. J Appl Physiol 88: 2246-2250, 2000.
112. Wang L, Pare PD, and Seow CY. Selected Contribution: Effect of chronic passive length change on airway smooth muscle length-tension relationship. J Appl Physiol 90: 734-740, 2001.
113. Whicker SD, Armour CL, and Black JL. Responsiveness of bronchial smooth muscle from asthmatic patients to relaxant and contractile agonists. Pulm Pharmacol 1: 25-31, 1988.
114. Wiggs BR, Hrousis CA, Drazen JM, and Kamm RD. On the mechanism of mucosal folding in normal and asthmatic airways. J Appl Physiol 83: 1814-1821, 1997.
115. Wilson JW and Li X. The measurement of reticular basement membrane and submucosal collagen in the asthmatic airway. Clin Exp Allergy 27: 363-371, 1997.
116. Wilson JW, Li X, and Pain MCF. The lack of distensibility of asthmatic airways. Am Rev Respir Dis 148: 806-809, 1993.
117. Woolcock AJ and Read J. The static elastic properties of the lungs in asthma. Am Rev Respir Dis 98: 788-794, 1968.
118. Woolcock AJ, Salome CM, and Yan K. The shape of the dose-response curve to histamine in asthmatic and normal subjects. Am Rev Respir Dis 130: 71-75, 1984.
119. Xu JQ, Gillis JM, and Craig R. Polymerization of myosin on activation of rat anococcygeus smooth muscle. J Muscle Res Cell Motil 18: 381-393, 1997.
120. Zhu YK, Liu X, Wang H, Kohyama T, Wen FQ, Skold CM, and Rennard SI. Interactions between monocytes and smooth-muscle cells can lead to extracellular matrix degradation. J Allergy Clin Immunol 108: 989-996, 2001.