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Selective Inflammatory Response Induced by Intratracheal and Intravenous Administration of Poly-L-Arginine in Guinea Pig Lungs

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Abstract

Major basic protein (MBP) is a cationic protein found in eosinophil granules that was postulated to participate in the pathogenesis of bronchial asthma. Recently, it has been demonstrated that MBP level in serum or bronchoalveolar lavage (BAL) fluid was correlated with bronchial hyperresponsiveness (BHR) in asthmatics. A number a studies have established that MBP actions could be mimicked by synthetic polycations as poly-L-arginine. In this study, we investigated the effects of intratracheal and intravenous administration of poly-L-arginine on lung inflammatory response development. The intratracheal injection of poly-L-arginine at the doses of 1, 10, 100 nmol/animal increased the number of eosinophils (up to 3.2 fold) and neutrophils (up to 12 fold) in BAL fluid. Eosinophil and neutrophil infiltration was reversed by 88% and 67% respectively following low molecular weight heparin treatment (500 μg/animal). The intravenous injection of increasing doses of poly-L-arginine (1, 10, 100, 500 nmol/animal) increased the number of eosinophils (up to 2.7 fold) but not neutrophil infiltration in guinea pig lungs. Eosinophil infiltration was reversed by 87% following low molecular weight heparin treatment (1.5 mg/animal). Intratracheal treatment with poly-L-arginine (100 nmol/animal) produced an important increase of β-glucuronidase, histamine, eosinophil peroxidase (EPO) and albumin levels in BAL fluid, whereas the intravenous treatment (500 nmol/animal) did not. These results show that the route of administration of poly-L-arginine greatly influences its effect on inflammatory cell recruitment since both administration routes elicited eosinophil migration but only the intratracheal route stimulated the migration of neutrophils. Moreover, poly-L-arginine appeared to induce other inflammatory responses since it increased β-glucuronidase, histamine, EPO and albumin levels in BAL fluid following intratracheal treatment. These results also showed that low molecular weight heparin significantly blocks the inflammatory responses elicited by poly-L-arginine.

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REFERENCES

  1. Kroegel, C. 1990. The role of eosinophils in asthma. Lung Suppl:5-17.

    Google Scholar 

  2. Spicer, B. A., R. Baker, S. M. Laycock, and H. Smith. 1989. Correlation between blood eosinophilia and airways hyper-responsiveness in rats. Agents and Actions 26:63-65.

    Google Scholar 

  3. Strek, M. E., S. R. White, T. R. Hsiue, G. V. P. Kulp, F. S. Williams, and A. R. Leff. 1993. Effect of mode of activation of human eosinophils on tracheal smooth muscle contraction in guinea pigs. Am. Physiol. Soc. 264:L475-L481.

    Google Scholar 

  4. Wardlaw, A. J., and A. B. Kay. 1987. The role of the eosinophil in the pathogenesis of asthma. Allergy 42:321-335.

    Google Scholar 

  5. Kroegel, C., J. C. Virchow, Jr., C. Kortsik, and H. Matthys. 1992. Cytokines, platelet activating factor and eosinophils in asthma. Respir. Med. 86:375-389.

    Google Scholar 

  6. Wasmoen, T. L., M. P. Bell, D. A. Loegering, G. J. Gleich, F. G. Prendergast, and D. J. McKean. 1988. Biochemical and amino acid sequence analysis of human eosinophil granule major basic protein. J. Biol. Chem. 263:12559-12563.

    Google Scholar 

  7. Lewis, D. M., J. C. Lewis, D. A. Loegering, and G. J. Gleich. 1978. Localization of the guinea pig eosinophil major basic protein to the core of the granule. J. Cell. Biol. 77:702-713.

    Google Scholar 

  8. Gleich, G. J., D. A. Loegering, and J. E. Maldonado. 1973. Identification of a major basic protein in guinea pig eosinophil granules. J. Exp. Med. 137:1459.

    Google Scholar 

  9. Gleich, G. J., D. A. Loegering, F. Kueppers, S. P. Bajaj, and K. G. Mann. 1974. Physiochemical and biological properties of the major basic protein from guinea pig eosinophil granules. J. Exp. Med. 140:313.

    Google Scholar 

  10. Abu-Ghazaleh, A. R., S. L. Dunnette, T. D. Krebs, and G. J. Gleich. 1987. Quantities of individual granule proteins in human eosinophils. J. Allergy Clin. Immunol. 79:162 (Abstr.)

    Google Scholar 

  11. Hamann, K. J., G. J. Gleich, R. H. Gundel, and S. R. White. 1991. Interactions between respiratory epithelium and eosinophil granule proteins in asthma: the eosinophil hypothesis. In: Farmer, S. G., and Hay, D. W. P. (editors). The Airway Epithelium, Physiology, Pathophysiology and Pharmacology. New York Marcel Dekker Inc, vol. 55. pp. 255-300.

  12. Frigas, E., D. A. Loegering, G. O. Solley, G. M. Farrow., and G. J. Gleich. 1981. Elevated levels of the eosinophil granule major basic protein in the sputum of patients with bronchial asthma. Mayo Clin. Proc. 56:345-353.

    Google Scholar 

  13. Wassom, D. L., D. A. Loegering, G. O. Solley, S. B. Moore, R. T. Schooley, A. S. Fauci, and G. J. Gleich. 1981. Elevated serum levels of the eosinophil granule major basic protein in patients with eosinophilia. J. Clin. Invest. 67:651-661.

    Google Scholar 

  14. White, R., K. S. Sigrist, and A. M. Spaethe. 1993. Prostaglandin secretion by guinea pig tracheal epithelial cells caused by eosinophil major basic protein. Am. J. Physiol. 265:L234-L242.

    Google Scholar 

  15. Hastie, A. T., D. A. Loegering, G. J. Gleich, and F. Kueppers, 1987. The effect of purified human eosinophil major basic protein on mammalian ciliary activity. Am. Rev. Respir. Dis. 135:848-853.

    Google Scholar 

  16. Gleich, G. J., N. A. Flavahan, T. Fujisawa, and P. M. Vanhoutte. 1988. The eosinophil as a mediator of damage to respiratory epithelium: a model for bronchial hyperreactivity. J. Allergy Clin. Immunol. 81:776-781.

    Google Scholar 

  17. Motojima, S., E. Frigas, D. A. Loegering, and G. J. Gleich. 1989. Toxicity of eosinophil cationic proteins for guinea pig tracheal epithelium in vitro. Am. Rev. Respir. Dis. 139:801-805.

    Google Scholar 

  18. Zheutlin, L. M., S. J. Ackerman, G. J. Gleich, and L. L. Thomas, 1984. Stimulation of basophil and rat mast cell histamine release by eosinophils granule-derived cationic proteins. J. Immunol. 133:2180-2185.

    Google Scholar 

  19. O'Donnell, M. A., S. J. Ackerman, G. J. Gleich, and L. L. Thomas. 1993. Activation of basophil and mast cell histamine release by eosinophil granule major basic protein. J. Exp. Med. 157:1981-1991.

    Google Scholar 

  20. White, S. R., S. Ohno, N. M. Munoz, G. J. Gleich, C. Abrahams, J. Solway, and A. R. Leff. 1990. Epithelium-dependent contraction of airway smooth muscle caused by eosinophil MBP. Am. J. Physiol. 259:L294-L303.

    Google Scholar 

  21. Gundel, R. H., G. Letts, and G. J. Gleich. 1991. Human eosinophil major basic protein induce airway constriction and airway hyperresponsiveness in primates. J. Clin. Invest. 87:1470-1473.

    Google Scholar 

  22. Dessai, S. N., G. Van, J. Robson, L. G. Letts, R. H. Gundel, G. J. Gleich, P. J. Piper, and T. C. Noonan. 1993. Human eosinophil major basic protein augments bronchoconstriction induced by intravenous agonists in guinea pigs. Agents and Actions 39:C132-C135.

    Google Scholar 

  23. Needham, L., P. J. Hellewell, T. J. Williams, and J. L. Gordon. 1988. Endothelial functional responses and increased vascular permeability induced by polycations. Lab. Invest. 59:538-548.

    Google Scholar 

  24. Uchida, D. A., S. J. Ackerman, A. J. Coyle, G. L. Larsen, P. F. Weller, J. Freed, and C. G. Irvin. 1993. The effect of human eosinophil granule major basic protein on airway responsiveness in the rat in vivo. Am. Rev. Respir. Dis. 147:982-988.

    Google Scholar 

  25. Coyle, A. J., S. J. Ackerman, C. G. Irvin. 1993. Cationic proteins induce airway hyperresponsiveness dependent on charge interactions. Am. Rev. Respir. Dis. 147:896-900.

    Google Scholar 

  26. Brofman, J. D., S. R. White, J. S. Blake, N. M. Munoz, G. J. Gleich, and A. R. Leff. 1989. Epithelial augmentation of trachealis contraction caused by major basic protein of eosinophils. J. Appl. Physiol. 66:1867-1873.

    Google Scholar 

  27. Spina, D., and R. G. Goldie. 1994. Contractile properties of synthetic cationic polypeptides in guinea-pig isolated trachea. Br. J. Pharmacol. 111:29-34.

    Google Scholar 

  28. Foreman, J., and L. M. Lichtenstein. 1980. Induction of histamine secretion by polycations. Biochem. Biophys. Acta. 629:587-603.

    Google Scholar 

  29. Leung, K. B. P., and F. L. Pearce. 1984. A comparison of histamine secretion from peritoneal mast cells of the rat and hamster. Br. J. Pharmacol. 81:693-701.

    Google Scholar 

  30. Church, M. K., G. J. K. Pao, and S. T. Holgate. 1982. Characterization of histamine secretion from mechanically dispersed human lung cells: effects of anti-IgE, calcium ionophore A23187, compound 48/80, and basic polypeptides. J. Immunol. 129:2116-2121.

    Google Scholar 

  31. Coyle, A. J., W. Mitzner, and C. G. Irvin. 1993. Cationic proteins alter smooth muscle function by an epithelium-dependent mechanism. Am. Physiol. Soc. 74:1761-1768.

    Google Scholar 

  32. Herbert, C. A., D. Edwards, J. R. Boot, and C. Robinson. 1991. In vitro modulation of the eosinophil-dependent enhancement of the permeability of the bronchial mucosa. Br. J. Pharmacol. 104:391-398.

    Google Scholar 

  33. Yu, X. Y., B. H. Schofield, T. Croxton, and E. W. Spannhake. 1992. Characteristics and mediation of the increased permeability of cultured canine bronchial epithelial cells induced by the cationic protein, poly-L-lysine. Am. Rev. Respir. Dis. 145:A355. (abstr.)

    Google Scholar 

  34. Vehaskari, V. M., V. T. C. Chang, J. K. Stevens, and A. M. Robson. 1984. The effects of polycations on vascular permeability in the rat. A proposed role for charge sites. J. Clin. Invest. 73:1053-1061.

    Google Scholar 

  35. Antunes, E., M. Mariano, G. Cirino, S. Levin, and G. De Nucci. 1990. Pharmacological characterization of polycation-induced rat hind paw oedema. Br. J. Pharmacol. 101:986-990.

    Google Scholar 

  36. Shier, W. T., D. J. Dubourdieu, and J. P. Dunrkin. 1984. Polycations as prostaglandin synthesis inducers. Stimulation of arachidonic acid release and prostaglandin synthesis in cultured fibroblasts by poly(L-lysine) and other synthetic polycations. Biochem. Biophys. Acta. 793:238-250.

    Google Scholar 

  37. Santana, A., S. Hyslop, E. Antunes, M. Mariano, Y. S. Bakhle, and G. De Nucci. 1993. Inflammatory responses induced by poly-L-arginine in rat lungs in vivo. Agents and Actions 39:104-110.

    Google Scholar 

  38. Fishman, W. H., K. Kato, C. L. Anstiss, and S. Green. 1967. Human serum β-glucuronidase: its measurement and some of its properties. Clin. Chim. Acta. 15:435-447.

    Google Scholar 

  39. Marwaha, R. K., B. F. Johnson, and G. E. Wright. 1985. Simple stability-indicating assay for histamine solutions. Am. J. Hosp. Pharm. 42:1568-1571.

    Google Scholar 

  40. Strath, M., D. J. Warren, and C. J. Sanderson. 1985. Detection of eosinophils using an eosinophil peroxidase assay. Its use as an assay for eosinophil differentiation factors. J. Immunol. Methods 83:209-215.

    Google Scholar 

  41. Doumas, B. T., W. A. Watson, and G. B. Homer. 1970. Albumin standards and the measurement of serum albumin with bromocresol green. Clin. Chim. Acta 31:87-96.

    Google Scholar 

  42. Gundel, R. H., M. E. Gerritsen, G. J. Gleich, and C. D. Wegner. 1990. Repeated antigen inhalation results in a prolonged airway eosinophilia and airway hyperresponsiveness in primates. J. Appl. Physiol. 68(2):779-786.

    Google Scholar 

  43. Perianin, A., and R. Snyderman. 1989. Mastoporan, a wasp venom peptide, identifies two discrete mechanisms for elevating cytosolic calcium and inositol triphosphates in human polymorphonuclear leukocytes. J. Immunol. 143:1669-1673.

    Google Scholar 

  44. Argiolas, A., and J. J. Pisano. 1983. Facilitation of phospholipase A2 activity by mastoporans, a new class of mast cell degranulating peptides from wasp venom. J. Biol. Chem. 258:13697-13702.

    Google Scholar 

  45. Kroegel, C., M. Giembycz, and P. J. Barnes. 1990. Characterization of eosinophil cell activation by peptides. Differential effects of substance P, melittin, and fMet-Leu-Phe. J. Immunol. 145:2581-2587.

    Google Scholar 

  46. Niggemann, B., I. Kleinau, M. Schmitt, and U. Wahn. 1994. Twenty-four hour time course of eosinophil granule proteins ECP and EPX during bronchial allergen challenges in serum of asthmatic children. Allergy 49:74-80.

    Google Scholar 

  47. Hamacher, J., and T. Schaberg. 1994. Adhesion molecules in lung diseases. Lung 172:189-213.

    Google Scholar 

  48. Ohkawara, Y., K. Yamauchi, N. Maruyama, H. Hoshi, I. Ohno, M. Honma, Y. Tanno, G. Tamura, K. Shirato, and H. Ohtani. 1995. In situ expression of the cell adhesion molecules in bronchial tissues from asthmatics with air flow limitation: in vivo evidence of VCAM-1/VLA-4 interaction in selective eosinophil infiltration. Am. J. Respir. Cell. Mol. Biol. 12:4-12.

    Google Scholar 

  49. Walls, A. F., Y. K. Rhee, D. J. Gould, C. Walters, C. Robinson, M. K. Church, and S. T. Holgate. 1991. Inflammatory mediators and cellular infiltration of the lungs in a guinea pig model of the late asthmatic reaction. Lung 169:227-240.

    Google Scholar 

  50. Marshall, T., P. Shult, and W. W. Busse. 1988. Release of lysosomal enzyme β-glucuronidase from isolated human eosinophils. J. Allergy Clin. Immunol. 82:550-555.

    Google Scholar 

  51. Schwartz, L. B., R. A. Lewis, D. Seldin, and K. F. Austen. 1981. Acid hydrolases and tryptase in secretory granules of dispersed lung mast cells. J. Immunol. 126:1290-1294.

    Google Scholar 

  52. Kita, H., R. I. Abu-Ghazaleh, S. Sur, and G. J. Gleich. 1995. Eosinophil Major Basic Protein Induces Degranulation and Il-8 Production by Human Eosinophils. J. Immunol. 154:4749-4758.

    Google Scholar 

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  1. Institut de Pharmacologie de Sherbrooke, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, P.Q., Canada, J1H 5N4

    Daniel Arseneault,  Maghni & Pierre Sirois

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Arseneault, D., Maghni & Sirois, P. Selective Inflammatory Response Induced by Intratracheal and Intravenous Administration of Poly-L-Arginine in Guinea Pig Lungs. Inflammation 23, 287–304 (1999). https://doi.org/10.1023/A:1020282205041

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