Abstract
A model of acute lung injury induced by intravenous phorbol myristate acetate (PMA) is described. The model is characterized by the accumulation of polymorphonuclear leukocytes (PMNs) and a hemorrhagic edema in bronchoalveolar lavage (BAL) fluid when measured 6 h following the administration of PMA (60 μg/kg, i.v.). It was also determined that PMA induces acute leukopenia and neutropenia which were maximal at 5 min following the injection of PMA and were sustained for at least 6 h, with circulating leukocyte numbers returning to control values by 24 h. The extents to which the inflammatory and systemic changes induced by PMA were dependent on the surface expression on leukocytes of the β2-integrins was assessed by comparing responses to PMA in control animals and animals pretreated with the anti-CD18 monoclonal antibody IB4. The administration of IB4 (1 mg/kg, i.v.) 15 min before PMA did not alter the time course or extent of PMA-induced leukopenia and neutropenia. In contrast IB4 administration (0.1 to 1 mg/kg) produced a dose dependent inhibition of PMN accumulation and plasma extravasation measured in BAL fluid. IB4 (1 mg/kg) completely inhibited PMA evoked increases in plasma extravasation (94.5 ± 1.7%, N = 4) and hemorrhage (95.2 ± 2.1%, N = 4) whereas PMN accumulation in BAL fluid was inhibited by 77.8 ± 3.8% (mean ± SEM, N = 4). Thus, a small, but reproducible, component of the PMA-induced PMN accumulation was not inhibited using this regimen of IB4 administration. If IB4 administration was delayed for 3 h post injection of PMA and bronchoalveolar lavage performed 3 h later, the extents of PMN accumulation and edema formation were similar to those observed 3 h following PMA challenge in control animals not dosed with IB4. This suggests that administration of IB4 during an ongoing inflammatory response is capable of preventing the further development of inflammatory changes and further supports the therapeutic potential of CD18 blockade in conditions such as adult respiratory distress syndrome.
Similar content being viewed by others
REFERENCES
Dal Nogare, A. R. 1989. Southwestern Internal Medical Conference: Adult Respiratory Distress Syndrome. Am. J. Med. Sci. 298:413–430.
Johnson, A., and A. B. Malik, 1980. The effects of granulocytopenia on extravascular lung water content after microembolization. Am. Rev. Respir. Dis. 122:561–566.
Modig, J., and T. Samuelsson. 1987. Prevention by granulocyte depletion of endotoxin-induced adult respiratory distress syndrome. An experimental study in pigs. Resuscitation 15:187–199.
Hinson, J. M., Jr., A. A. Hutchison, M. L. Ogletree, K. L. Brigham, and J. R. Snapper. 1983. Effect of granulocyte depletion on altered lung mechanics after endotoxemia in sheep. J. Appl. Physiol. 55:92–99.
Walsh, C. J., P. C. Carey, D. J. Cook, D. E. Bechard, A. A. Fowler, and H. J. Sugerman. 1991. Anti-CD18 antibody attenuates neutropenia and alveolar capillary-membrane injury during gram-negative sepsis. Surgery 110:205–212.
Gie, R. P., C. M. Doerschuk, D. English, H. O. Coxson, and J. C. Hogg. 1991. Neutrophil-associated lung injury after the infusion of activated plasma. J. Appl. Physiol. 70:2471–2478.
Patarroyo, M. 1991. Leukocyte adhesion in host defense and tissue injury. Clin. Immunol. Immunopathol. 60:333–348.
Bevilacqua, M. P., S. Stengelin, M. A. Gimbrone, Jr., and B. Seed. 1989. Endothelial leukocyte adhesion molecule I: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science 243:1160–1165.
Geng, J. G., M. S. Bevilacqua, K. L. Moore, T. M. McIntyre, S. M. Prescott, J. M. Kim, G. A. Bliss, G. A. Zimmerman, and R. P. McEver. 1990. Rapid neutrophil adhesion to activated endothelium mediated by GMP-140. Nature 343:575–760.
Doerschuk, C. M., R. K. Winn, H. O. Coxson, and J. M. Harlan. 1990. CD18-dependent and-independent mechanisms of neutrophil emigration in the pulmonary and systemic micro-circulation of rabbits. J. Immunol. 144:2327–2333.
Williams, T. J., P. J. Jose, M. J. Forrest, C. V. Wedmore, and G. F. Clough. 1984. Interactions between neutrophils and microvascular endothelial cells leading to cell emigration and plasma protein leakage. In White cell mechanics: basic silence and clinical aspects. H. J. Meiselman, M. A. Lichtman, and P. L. LeCelle, (editors). Alan R. Liss, Inc., New York, NY. 195–208.
Ward, P. A. and J. Varani. 1990. Mechanisms of neutrophil-mediated killing of endothelial cells. J. Leuk. Biol. 48:97–102.
Issekutz, A. C. and H. A. Movat. 1980. The in vitro quantitation and kinetics of rabbit neutrophil leukocyte accumulation in the skin in response to chemotactic agents and escherichia coli. Lab. Invest. 42:310–317.
Wright, S. D., P. E. Rao, W. C. Van Voorhis, L. S. Craigmyle, K. Iida, M. A. Talle, E. F. Westberg, G. Goldstein, and S. C. Silverstein. 1983. Identification of the C3bi receptor of human monocytes and macrophages by using monoclonal antibodies. Proc. Natl. Acad. Sci. U.S.A. 80:5699–5703.
Lundberg, C., and Wright, S. D. 1990. Relation of the CD11/CD18 family of leukocyte antigens to the transient neutropenia caused by chemoattractants. Blood 76:1240–1245.
Barton, R. W., R. Rothlein, J. Ksiazek, and C. Kennedy, 1989. The effects of antiinter-cellular adhesion molecule-1 on phorbol-ester-induced rabbit lung inflammation. J. Immunol. 143:1278–1282.
Springer, T. A. 1995. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu. Rev. Physiol. 57:827–872.
Ley, K. 1996. Molecular mechanisms of leukocyte recruitment in the inflammatory process. Cardiovasc. Res. 32:733–742.
Butcher, E. C. 1991. Leukocyte-endothelial cell recognition—three (or more) steps to specificity and diversity. Cell. 67:1033–1036.
Springer, T. A. 1994. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 76:301–314.
Mileski, W., J. Harlan, C. Rice, and R. Winn. 1990. Streptococcus pneumoniae-stimulated macrophages induce neutrophils to emigrate by a CD18-independent mechanism of adherence. Circ. Shock. 31:259–267.
Overdahl, M. C., M. W. Julian, S. E. Weisbrode, and P. M. Dorinsky. 1995. Anti-CD18 antibody does not block ileal injury induced by phorbol myristate acetate. Am. J. Respir. Crit. Care Med. 152:1331–1336.
Mulligan, M. S., Lentsch, A. B., and Ward, P. A. 1998. In vivo recruitment of neutrophils: consistent requirements for L21-Arginine and variable requirements for complement and adhesion molecules. Inflammation 22:327–339.
Hawkins, H. K., Heffelfinger, S. C., and Anderson, D. C. 1992. Leukocyte adhesion deficiency: clinical and postmorten observations. Pediatr. Pathol. 12:119–130.
Lo, S. K., R. Rene, G. Szabo, and A. B. Malik. 1990. Leukocyte repletion reverses protective effect of neutropenia in thrombin-induced increase in lung vascular permeability. Am. J. Physiol. 259:H149-H155.
horgan, m. j., wright, s. d., and malik, a. b. 1990. antibody against leukocyte integrin (cd18) prevents reperfusion-induced lung vascular injury. am. j. physiol. 259:l315-l319.
Majno, G. E., Shea, S. M., and Leventhal, M. 1969. Endothelial contraction induced by histamine-type mediators. An electron microscopic study. J. Cell. Biol. 42:647–672.
Jackson, J. H., C. W. White, I. F. McMurtry, E. M. Berger, and J. E. Repine. 1986. Dimethylthiourea decreases acute lung edema in phorbol myristate acetate-treated rabbits. J. Appl. Physiol. 61:353–360.
Shasby, D. M., K. M. Vanbenthuysen, R. M. Tate, S. S. Shasby, I. McMurtry, and J. E. Repine. 1982. Granulocytes mediate acute edematous lung injury in rabbits and in isolated rabbit lungs perfused with phorbol myristate acetate: role of oxygen radicals. Am. Rev. Respir. Dis. 125:443–447.
O'Flaherty, J. T., H. J. Showell, and P. A. Ward. 1977. Neutropenia induced by systemic infusion of chemotactic factors. J. Immunol. 118:1586–1589.
Worthen, G. S., B. Schwab, III, E. L. Elson, and G. P. Downey. 1989. Mechanics of stimulated neutrophils: cell stiffening induces retention in capillaries. Science 245:183–186.
von Andrian, U. H., J. D. Chambers, L. M. McEvoy, R. F. Bargatze, K. E. Arfors, and Btcher, E. C. 1991. Two-step model of leukocyte endothelial cell interaction in inflammation—distinct roles for LECAM-1 and the leukocyte beta 2 integrins in vivo. Proc. Natl. Acad. Sci. (U.S.A) 88:7538–7542.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Meurer, R.D., Forrest, M.J. & Macintyre, D.E. The Effects of IB4, a Monoclonal Antibody to the CD18 Leukocyte Integrin on Phorbol Myristate Acetate (PMA)-Induced Polymorphonuclear Leukocyte (PMN) Accumulation and Endothelial Injury in Rabbit Lungs. Inflammation 23, 51–62 (1999). https://doi.org/10.1023/A:1020239600981
Issue Date:
DOI: https://doi.org/10.1023/A:1020239600981