Journal Mobile Options
Table of Contents
Vol. 89, No. 3, 2006
Issue release date: April 2006
Biol Neonate 2006;89:159–170
(DOI:10.1159/000088843)

Effects of an Intratracheally Delivered Anti-Inflammatory Protein (rhCC10) on Physiological and Lung Structural Indices in a Juvenile Model of Acute Lung Injury

Miller T.L. · Shashikant B.N. · Pilon A.L. · Pierce R.A. · Shaffer T.H. · Wolfson M.R.
aDepartment of Physiology, Temple University School of Medicine, Philadelphia, Pa., bNemours Research Lung Center, Alfred I. duPont Hospital for Children, Wilmington, Del., cClaragen, Inc., College Park, Md., and dPulmonary and Critical Care Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Mo., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

Background: Mechanical ventilation results in acute lung trauma that can stimulate processes that alter lung development. Activation of matrix metalloproteinases (MMPs) and their tissue-produced inhibitors (TIMPs) is initiated by the inflammatory response to mechanical ventilation and are involved in breakdown of the basement membrane and parenchymal modeling. Objectives: The aim of this study was to test the hypothesis that rhCC10, a lung anti-inflammatory mediator, would foster improved lung function, structural preservation, and a reduction in net MMP activity in a juvenile model of acute lung injury. Methods: Twenty-four juvenile rabbits were saline-lavage-injured and treated with 100 or 25 mg/kg surfactant (Survanta®, Ross Labs) with or without rhCC10 (Claragen, Inc.; n = 6 per group). Animals were ventilated for 4 h, then euthanized for in vitro surfactant function analysis, lung histomorphometry, and analysis of MMP-2, MMP-7, and MMP-9 and TIMPs 1 and 2 in the lung. Results: Apical lung expansion, reduced with the lower dose of surfactant, was partially restored with the addition of rhCC10. Alveolar septal wall thickness was reduced (p < 0.05) with low-dose surfactant plus rhCC10 compared to high-dose surfactant alone. Increased within-group variance in MMP-2 and MMP-9 proteolytic activity was found with the low-dose surfactant and was abolished with rhCC10. MMP-7 was reduced (p < 0.05) with rhCC10 administration, independent of surfactant dose. Conclusions: Intratracheal administration of the anti-inflammatory rhCC10 resulted in preserved lung structure and MMP/TIMP profile after 4 h of mechanical ventilation, in a surfactant dose-dependent manner.



Copyright / Drug Dosage

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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

References

  1. Chen P, Xiang XD, Lu YD: Low volume mechanical ventilation in the treatment of patients with chronic obstructive lung diseases with type II respiratory failure [in Chinese]. Bulletin of Hunan Medical University 2000;25:53–54.
  2. Rouby JJ, Lherm T, Martin de Lassale E, Poete P, Bodin L, Finet JF, Callard P, Viars P: Histologic aspects of pulmonary barotrauma in critically ill patients with acute respiratory failure. Intensive Care Med 1993;19:383–389.
  3. Goldstein I, Bughalo MT, Marquette CH, Lenaour G, Lu Q, Rouby JJ, Experimental ICUSG: Mechanical ventilation-induced air-space enlargement during experimental pneumonia in piglets. Am J Respir Crit Care Med 2001;163:958–964.
  4. Nagase H, Woessner JF Jr: Matrix metalloproteinases. J Biol Chem 1999;274:21491–21494.
  5. Parks WC, Shapiro SD: Matrix metalloproteinases in lung biology. Respir Res 2001;2:10–19.
  6. Ikegami M, Jobe A, Jacobs H, Lam R: A protein from airways of premature lambs that inhibits surfactant function. J Appl Physiol 1984;57:1134–1142.
  7. Ueda T, Ikegami M, Jobe A: Surfactant subtypes. In vitro conversion, in vivo function, and effects of serum proteins. Am J Respir Crit Care Med 1994;149:1254–1259.
  8. Holm BA, Notter RH: Effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity. J Appl Physiol 1987;63:1434–1442.
  9. Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003;92:827–839.
  10. Kheradmand F, Rishi K, Werb Z: Signaling through the EGF receptor controls lung morphogenesis in part by regulating MT1-MMP-mediated activation of gelatinase A/MMP2. J Cell Sci 2002;115(Pt 4):839–848.
  11. Infeld MD: Cell-matrix interactions in gland development in the lung. Exp Lung Res 1997;23:161–169.
  12. Fukuda Y, Ishizaki M, Okada Y, Seiki M, Yamanaka N: Matrix metalloproteinases and tissue inhibitor of metalloproteinase-2 in fetal rabbit lung. Am J Physiol Lung Cell Mol Physiol 2000;279:L555–L561.
  13. D’Ortho MP, Jarreau PH, Delacourt C, Macquin-Mavier I, Levame M, Pezet S, Harf A, Lafuma C: Matrix metalloproteinase and elastase activities in LPS-induced acute lung injury in guinea pigs. Am J Physiol 1994;266(3 Pt 1):L209–L216.
  14. Gibbs DF, Shanley TP, Warner RL, Murphy HS, Varani J, Johnson KJ: Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury. Evidence for alveolar macrophage as source of proteinases. Am J Respir Cell Mol Biol 1999;20:1145–1154.
  15. Keck T, Balcom JHt, Fernandez-del Castillo C, Antoniu BA, Warshaw AL: Matrix metalloproteinase-9 promotes neutrophil migration and alveolar capillary leakage in pancreatitis-associated lung injury in the rat. Gastroenterology 2002;122:188–201.
  16. Allan JA, Docherty AJ, Barker PJ, Huskisson NS, Reynolds JJ, Murphy G: Binding of gelatinases A and B to type-I collagen and other matrix components. Biochem J 1995;309(Pt 1):299–306.
  17. Murphy G, Nguyen Q, Cockett MI, Atkinson SJ, Allan JA, Knight CG, Willenbrock F, Docherty AJ: Assessment of the role of the fibronectin-like domain of gelatinase A by analysis of a deletion mutant. J Biol Chem 1994;269:6632–6636.
  18. Shipley JM, Doyle GA, Fliszar CJ, Ye QZ, Johnson LL, Shapiro SD, Welgus HG, Senior RM: The structural basis for the elastolytic activity of the 92-kDa and 72-kDa gelatinases. Role of the fibronectin type II-like repeats. J Biol Chem 1996;271:4335–4341.
  19. Dunsmore SE, Saarialho-Kere UK, Roby JD, Wilson CL, Matrisian LM, Welgus HG, Parks WC: Matrilysin expression and function in airway epithelium. J Clin Invest 1998;102:1321–1331.
  20. Li Q, Park PW, Wilson CL, Parks WC: Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 2002;111:635–646.
  21. Wilson CL, Matrisian LM: Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol 1996;28:123–136.
  22. Pardo A, Selman M: Matrix metalloproteinases and lung injury. Braz J Med Biol Res 1996;29:1109–1115.
  23. Chandra S, Davis JM, Drexler S, Kowalewska J, Chester D, Koo HC, Pollack S, Welch R, Pilon A, Levine CR: Safety and efficacy of intratracheal recombinant human Clara cell protein in a newborn piglet model of acute lung injury. Pediatr Res 2003;54:509–515.
  24. Ryerse JS, Hoffmann JW, Mahmoud S, Nagel BA, deMello DE: Immunolocalization of CC10 in Clara cells in mouse and human lung. Histochem Cell Biol 2001;115:325–332.
  25. Chen LC, Zhang Z, Myers AC, Huang SK: Cutting edge: altered pulmonary eosinophilic inflammation in mice deficient for Clara cell secretory 10-kDa protein. J Immunol 2001;167:3025–3028.
  26. Pilon AL: Rationale for the development of recombinant human CC10 as a therapeutic for inflammatory and fibrotic disease. Ann NY Acad Sci 2000;923:280–299.
  27. Levin SW, Butler JD, Schumacher UK, Wightman PD, Mukherjee AB: Uteroglobin inhibits phospholipase A2 activity. Life Sci 1986;38:1813–1819.
  28. Duncan JE, Hatch GM, Belik J: Susceptibility of exogenous surfactant to phospholipase A2 degradation. Can J Physiol Pharmacol 1996;74:957–963.
  29. Geerts L, Jorens PG, Willems J, De Ley M, Slegers H: Natural inhibitors of neutrophil function in acute respiratory distress syndrome. Crit Care Medi 2001;29:1920–1924.
  30. Miller TL, Nordby BA, Melby J, Pilon AL, Shaffer TH, Wolfson MR: Comparison of intratracheal (IT) vs intravenous (IV) administration of rhCC10 in acute lung injury (ALI): physiologic, inflammatory, and kinetic profiles. Pediatr Res 2002;51:464A.
  31. Miller TL, Shashikant BN, Pierce RA, Gaughan JP, Pilon AL, Shaffer TH, Wolfson MR: Intratracheal (IT) rhCC10 dose-response in neonatal RDS: impact on lung structure and function. Pediatr Res 2003;53:404A.

    External Resources

  32. Nordby BA, Miller TL, Melby J, Pilon AL, Shaffer TH, Wolfson MR: rhCC10-augmented surfactant (SF) therapy in acute lung injury (ALI): physiologic and inflammatory profile. Pediatr Res 2002;51:469A.
  33. Shashikant BN, Miller TL, Melby J, Pilon AL, Shaffer TH, Wolfson MR: Dose-response to rhCC10-augmented surfactant (SF) therapy in infant respiratory distress syndrome (RDS): inflammation and kinetic profiles. Pediatr Res 2003;53:463A.
  34. Levine CR, Gewolb KA, Welch R, Melby J, Pilon AL, Davis JM: Safety, pharmacokinetics and anti-inflammatory activity of rhCC10 in premature infants with respiratory distress syndrome (RDS). Pediatr Res 2005;58:15–21.
  35. Bhutani VK, Sivieri EM, Abbasi S, Shaffer TH: Evaluation of neonatal pulmonary mechanics and energetics: a two factor least mean square analysis. Pediatr Pulmonol 1988;4:150–158.
  36. Antunes MJ, Cullen JA, Holt WJ, Gauthier TW, Baumgart S, Greenspan JS: Continued pulmonary recovery observed after discontinuing extracorporeal membrane oxygenation. Pediatr Pulmonol 1994;17:143–148.
  37. Khan AM, Shabarek FM, Kutchback JW, Lally KP: Effects of dexamethasone on meconium aspiration syndrome in newborn piglets. Pediatr Res 1999;46:179–183.
  38. Notter RH, Egan EA, Kwong MS, Holm BA, Shapiro DL: Lung surfactant replacement in premature lambs with extracted lipids from bovine lung lavage: effects of dose, dispersion technique, and gestational age. Pediatr Res 1985;19:569–577.
  39. Bligh EG, Dyer WJ: A rapid method of total lipid extraction and purification. Can J Biochem Physiol 1959;37:911–917.
  40. Bartlett GR: Phosphorus assay in column chromatography. J Biol Chem 1959;234:466–468.
  41. Rouser G, Fleischer S, Yamamoto A: Two dimensional thin layer chromatographic separation of polar lipids and determination of phospholipids by phosphorus analysis of spots. Lipids 1970;5:494–496.
  42. Enhorning G: Pulsating bubble technique for evaluating pulmonary surfactant. J Appl Physiol 1977;43:198–203.
  43. Wolfson MR, Greenspan JS, Deoras KS, Rubenstein SD, Shaffer TH: Comparison of gas and liquid ventilation: clinical, physiological, and histological correlates. J Appl Physiol 1992;72:1024–1031.
  44. Wolfson MR, Kechner NE, Roache RF, DeChadarevian JP, Friss HE, Rubenstein SD, Shaffer TH: Perfluorochemical rescue after surfactant treatment: effect of perflubron dose and ventilatory frequency. J Appl Physiol 1998;84:624–640.
  45. Deoras KS, Wolfson MR, Searls RL, Hilfer SR, Sheffield JB, Shaffer TH: Use of a touch sensitive screen and computer assisted image analysis for quantitation of developmental changes in pulmonary structure. Pediatr Pulmonol 1990;9:109–118.
  46. Thomas CV, Coker ML, Zellner JL, Handy JR, Crumbley AJ, III, Spinale FG: Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation 1998;97:1708–1715.
  47. Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R, Hebbar L: Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: relation to ventricular and myocyte function. Circ Res 1998;82:482–495.
  48. Oliver GW, Leferson JD, Stetler-Stevenson WG, Kleiner DE: Quantitative reverse zymography: analysis of picogram amounts of metalloproteinase inhibitors using gelatinase A and B reverse zymograms. Anal Biochem 1997;244:161–166.
  49. Kijowski J, Baj-Krzyworzeka M, Majka M, Reca R, Marquez LA, Christofidou-Solomidou M, Janowska-Wieczorek A, Ratajczak MZ: The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells 2001;19:453–466.
  50. Wolf M, Klug J, Hackenberg R, Gessler M, Grzeschik KH, Beato M, Suske G: Human CC10, the homologue of rabbit uteroglobin: genomic cloning, chromosomal localization and expression in endometrial cell lines. Hum Mol Genet 1992;1:371–378.
  51. Goerke J: Pulmonary surfactant: functions and molecular composition. Biochim Biophys Acta 1998;1408:79–89.
  52. Possmayer F, Yu SH, Weber JM, Harding PG: Pulmonary surfactant. Canadian J Biochem Cell Biol 1984;62:1121–1133.
  53. Holm BA, Notter RH, Finkelstein JN: Surface property changes from interactions of albumin with natural lung surfactant and extracted lung lipids. Chem Phys Lipids 1985;38:287–298.
  54. Devlieger R, Riley SC, Verbist L, Leask R, Pijnenborg R, Deprest JA: Matrix metalloproteinases-2 and -9 and their endogenous tissue inhibitors in tissue remodeling after sealing of the fetal membranes in a sheep model of fetoscopic surgery. J Soc Gynecol Investig 2002;9:137–145.
  55. Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M: A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 1994;370:61–65.
  56. Butler GS, Butler MJ, Atkinson SJ, Will H, Tamura T, van Westrum SS, Crabbe T, Clements J, d’Ortho MP, Murphy G: The TIMP2 membrane type 1 metalloproteinase ‘receptor’ regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem 1998;273:871–880.
  57. Murphy G, Stanton H, Cowell S, Butler G, Knauper V, Atkinson S, Gavrilovic J: Mechanisms for pro matrix metalloproteinase activation. APMIS 1999;107:38–44.
  58. Gortner L, Pohlandt F, Bartmann P, Bernsau U, Porz F, Hellwege HH, Seitz RC, Hieronimi G, Kuhls E, Jorch G: High-dose versus low-dose bovine surfactant treatment in very premature infants. Acta Paediatr 1994;83:135–141.
  59. Su WY, Jaskot RH, Richards J, Abramson SR, Woessner JF Jr, Yu WH, Dreher KL: Induction of pulmonary matrilysin expression by combustion and ambient air particles. Am J Physiol Lung Cell Mol Physiol 2000;279:L152–L160.
  60. Winkler MK, Foldes JK, Bunn RC, Fowlkes JL: Implications for matrix metalloproteinases as modulators of pediatric lung disease. Am J Physiol Lung Cell Mol Physiol 2003;284:L557–L565.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50