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. 1997 May 1;99(9):2110–2117. doi: 10.1172/JCI119384

The role of alveolar macrophages in Pneumocystis carinii degradation and clearance from the lung.

A H Limper 1, J S Hoyte 1, J E Standing 1
PMCID: PMC508041  PMID: 9151783

Abstract

Although studies indicate that alveolar macrophages participate in host defense against Pneumocystis carinii, their role in organism degradation and clearance from the lung has not yet been established. We, therefore, quantified the uptake and degradation of 35S-labeled P. carinii by cultured macrophages, demonstrating significant degradation of P. carinii over 6 h. We further evaluated the role of macrophages in elimination of P. carinii from the living host. Rats received either intratracheal PBS, liposomal PBS (L-PBS), or liposomal dichloromethylene diphosphonate (L-Cl2MDP), a preparation which leads to selective depletion of macrophages. Over 72 h, L-Cl2MDP-treated animals had loss of > 85% of their alveolar macrophages. In contrast, L-PBS-treated rats had cellular differentials identical to rats receiving PBS. Macrophage-depleted rats and controls were next inoculated with P. carinii and organism clearance was determined after 24 h. P. carinii elimination was evaluated with both cyst counts and an ELISA directed against glycoprotein A (gpA), the major antigen of P. carinii. Both assays indicated that macrophage-depleted rats had substantial inpairment of P. carinii clearance compared to L-PBS- or PBS-treated rats. These data provide the first direct evidence that macrophages mediate elimination of P. carinii from the living host.

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Selected References

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  1. Armstrong M. Y., Koziel H., Rose R. M., Arena C., Richards F. F. Indicators of Pneumocystis carinii viability in short-term cell culture. J Protozool. 1991 Nov-Dec;38(6):88S–90S. [PubMed] [Google Scholar]
  2. Bartlett M. S., Fishman J. A., Queener S. F., Durkin M. M., Jay M. A., Smith J. W. New rat model of Pneumocystis carinii infection. J Clin Microbiol. 1988 Jun;26(6):1100–1102. doi: 10.1128/jcm.26.6.1100-1102.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bartlett M. S., Verbanac P. A., Smith J. W. Cultivation of Pneumocystis carinii with WI-38 cells. J Clin Microbiol. 1979 Dec;10(6):796–799. doi: 10.1128/jcm.10.6.796-799.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beck J. M., Warnock M. L., Curtis J. L., Sniezek M. J., Arraj-Peffer S. M., Kaltreider H. B., Shellito J. E. Inflammatory responses to Pneumocystis carinii in mice selectively depleted of helper T lymphocytes. Am J Respir Cell Mol Biol. 1991 Aug;5(2):186–197. doi: 10.1165/ajrcmb/5.2.186. [DOI] [PubMed] [Google Scholar]
  5. Berg J. T., Lee S. T., Thepen T., Lee C. Y., Tsan M. F. Depletion of alveolar macrophages by liposome-encapsulated dichloromethylene diphosphonate. J Appl Physiol (1985) 1993 Jun;74(6):2812–2819. doi: 10.1152/jappl.1993.74.6.2812. [DOI] [PubMed] [Google Scholar]
  6. Castro M., Morgenthaler T. I., Hoffman O. A., Standing J. E., Rohrbach M. S., Limper A. H. Pneumocystis carinii induces the release of arachidonic acid and its metabolites from alveolar macrophages. Am J Respir Cell Mol Biol. 1993 Jul;9(1):73–81. doi: 10.1165/ajrcmb/9.1.73. [DOI] [PubMed] [Google Scholar]
  7. Chen W., Havell E. A., Harmsen A. G. Importance of endogenous tumor necrosis factor alpha and gamma interferon in host resistance against Pneumocystis carinii infection. Infect Immun. 1992 Apr;60(4):1279–1284. doi: 10.1128/iai.60.4.1279-1284.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cohn D. L., Stover D. E., O'Brien R. F., Shelhamer J. H., Raffin T. A., Hopewell P. C. Pulmonary complications of AIDS: advances in diagnosis and treatment. Am Rev Respir Dis. 1988 Oct;138(4):1051–1052. [PubMed] [Google Scholar]
  9. Cushion M. T., DeStefano J. A., Walzer P. D. Pneumocystis carinii: surface reactive carbohydrates detected by lectin probes. Exp Parasitol. 1988 Dec;67(2):137–147. doi: 10.1016/0014-4894(88)90061-6. [DOI] [PubMed] [Google Scholar]
  10. Ezekowitz R. A., Williams D. J., Koziel H., Armstrong M. Y., Warner A., Richards F. F., Rose R. M. Uptake of Pneumocystis carinii mediated by the macrophage mannose receptor. Nature. 1991 May 9;351(6322):155–158. doi: 10.1038/351155a0. [DOI] [PubMed] [Google Scholar]
  11. Garraud O., Faucher A., Legrand E. Impairment of monocyte functions in advanced head and neck cancer. Immunol Lett. 1988 Jul;18(3):213–218. doi: 10.1016/0165-2478(88)90021-1. [DOI] [PubMed] [Google Scholar]
  12. Gigliotti F. Host species-specific antigenic variation of a mannosylated surface glycoprotein of Pneumocystis carinii. J Infect Dis. 1992 Feb;165(2):329–336. doi: 10.1093/infdis/165.2.329. [DOI] [PubMed] [Google Scholar]
  13. Gigliotti F., Stokes D. C., Cheatham A. B., Davis D. S., Hughes W. T. Development of murine monoclonal antibodies to Pneumocystis carinii. J Infect Dis. 1986 Aug;154(2):315–322. doi: 10.1093/infdis/154.2.315. [DOI] [PubMed] [Google Scholar]
  14. Haidaris P. J., Wright T. W., Gigliotti F., Haidaris C. G. Expression and characterization of a cDNA clone encoding an immunodominant surface glycoprotein of Pneumocystis carinii. J Infect Dis. 1992 Nov;166(5):1113–1123. doi: 10.1093/infdis/166.5.1113. [DOI] [PubMed] [Google Scholar]
  15. Hidalgo H. A., Helmke R. J., German V. F., Mangos J. A. Pneumocystis carinii induces an oxidative burst in alveolar macrophages. Infect Immun. 1992 Jan;60(1):1–7. doi: 10.1128/iai.60.1.1-7.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hoffman O. A., Standing J. E., Limper A. H. Pneumocystis carinii stimulates tumor necrosis factor-alpha release from alveolar macrophages through a beta-glucan-mediated mechanism. J Immunol. 1993 May 1;150(9):3932–3940. [PubMed] [Google Scholar]
  17. Huang Z. B., Eden E. Effect of corticosteroids on IL1 beta and TNF alpha release by alveolar macrophages from patients with AIDS and Pneumocystis carinii pneumonia. Chest. 1993 Sep;104(3):751–755. doi: 10.1378/chest.104.3.751. [DOI] [PubMed] [Google Scholar]
  18. Kolls J. K., Beck J. M., Nelson S., Summer W. R., Shellito J. Alveolar macrophage release of tumor necrosis factor during murine Pneumocystis carinii pneumonia. Am J Respir Cell Mol Biol. 1993 Apr;8(4):370–376. doi: 10.1165/ajrcmb/8.4.370. [DOI] [PubMed] [Google Scholar]
  19. Kovacs J. A., Powell F., Edman J. C., Lundgren B., Martinez A., Drew B., Angus C. W. Multiple genes encode the major surface glycoprotein of Pneumocystis carinii. J Biol Chem. 1993 Mar 15;268(8):6034–6040. [PubMed] [Google Scholar]
  20. Koziel H., Kruskal B. A., Ezekowitz R. A., Rose R. M. HIV impairs alveolar macrophage mannose receptor function against Pneumocystis carinii. Chest. 1993 Feb;103(2 Suppl):111S–112S. doi: 10.1378/chest.103.2_supplement.111s. [DOI] [PubMed] [Google Scholar]
  21. Koziel H., O'Riordan D., Warner A., Rose R. M. Alveolar macrophage interaction with Pneumocystis carinii. Immunol Ser. 1994;60:417–436. [PubMed] [Google Scholar]
  22. Krishnan V. L., Meager A., Mitchell D. M., Pinching A. J. Alveolar macrophages in AIDS patients: increased spontaneous tumour necrosis factor-alpha production in Pneumocystis carinii pneumonia. Clin Exp Immunol. 1990 May;80(2):156–160. doi: 10.1111/j.1365-2249.1990.tb05225.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Laursen A. L., Obel N., Rungby J., Andersen P. L. Phagocytosis and stimulation of the respiratory burst in neutrophils by Pneumocystis carinii. J Infect Dis. 1993 Dec;168(6):1466–1471. doi: 10.1093/infdis/168.6.1466. [DOI] [PubMed] [Google Scholar]
  24. Limper A. H., Martin W. J., 2nd Pneumocystis carinii: inhibition of lung cell growth mediated by parasite attachment. J Clin Invest. 1990 Feb;85(2):391–396. doi: 10.1172/JCI114451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Limper A. H., Offord K. P., Smith T. F., Martin W. J., 2nd Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS. Am Rev Respir Dis. 1989 Nov;140(5):1204–1209. doi: 10.1164/ajrccm/140.5.1204. [DOI] [PubMed] [Google Scholar]
  26. Limper A. H. Parasitic adherence and host responses in the development of Pneumocystis carinii pneumonia. Semin Respir Infect. 1991 Mar;6(1):19–26. [PubMed] [Google Scholar]
  27. Limper A. H., Pottratz S. T., Martin W. J., 2nd Modulation of Pneumocystis carinii adherence to cultured lung cells by a mannose-dependent mechanism. J Lab Clin Med. 1991 Nov;118(5):492–499. [PubMed] [Google Scholar]
  28. Limper A. H., Specks U., Brutinel W. M., Martin W. J., 2nd, Rohrbach M. S. Interlobar variation in the recovery of bronchoalveolar lavage fluid, cell populations, and angiotensin-converting enzyme in normal volunteers. J Lab Clin Med. 1993 Jun;121(6):785–791. [PubMed] [Google Scholar]
  29. Limper A. H., Standing J. E., Hoffman O. A., Castro M., Neese L. W. Vitronectin binds to Pneumocystis carinii and mediates organism attachment to cultured lung epithelial cells. Infect Immun. 1993 Oct;61(10):4302–4309. doi: 10.1128/iai.61.10.4302-4309.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Linke M. J., Cushion M. T., Walzer P. D. Properties of the major antigens of rat and human Pneumocystis carinii. Infect Immun. 1989 May;57(5):1547–1555. doi: 10.1128/iai.57.5.1547-1555.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lundgren B., Lipschik G. Y., Kovacs J. A. Purification and characterization of a major human Pneumocystis carinii surface antigen. J Clin Invest. 1991 Jan;87(1):163–170. doi: 10.1172/JCI114966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mason G. R., Hashimoto C. H., Dickman P. S., Foutty L. F., Cobb C. J. Prognostic implications of bronchoalveolar lavage neutrophilia in patients with Pneumocystis carinii pneumonia and AIDS. Am Rev Respir Dis. 1989 Jun;139(6):1336–1342. doi: 10.1164/ajrccm/139.6.1336. [DOI] [PubMed] [Google Scholar]
  33. Masur H., Jones T. C. The interaction in vitro of Pneumocystis carinii with macrophages and L-cells. J Exp Med. 1978 Jan 1;147(1):157–170. doi: 10.1084/jem.147.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Masur H., Lane H. C., Kovacs J. A., Allegra C. J., Edman J. C. NIH conference. Pneumocystis pneumonia: from bench to clinic. Ann Intern Med. 1989 Nov 15;111(10):813–826. doi: 10.7326/0003-4819-111-10-813. [DOI] [PubMed] [Google Scholar]
  35. McDonald J. A., Broekelmann T. J., Matheke M. L., Crouch E., Koo M., Kuhn C., 3rd A monoclonal antibody to the carboxyterminal domain of procollagen type I visualizes collagen-synthesizing fibroblasts. Detection of an altered fibroblast phenotype in lungs of patients with pulmonary fibrosis. J Clin Invest. 1986 Nov;78(5):1237–1244. doi: 10.1172/JCI112707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. McDonald J. A., Quade B. J., Broekelmann T. J., LaChance R., Forsman K., Hasegawa E., Akiyama S. Fibronectin's cell-adhesive domain and an amino-terminal matrix assembly domain participate in its assembly into fibroblast pericellular matrix. J Biol Chem. 1987 Mar 5;262(7):2957–2967. [PubMed] [Google Scholar]
  37. Murray J. F., Mills J. Pulmonary infectious complications of human immunodeficiency virus infection. Part II. Am Rev Respir Dis. 1990 Jun;141(6):1582–1598. doi: 10.1164/ajrccm/141.6.1582. [DOI] [PubMed] [Google Scholar]
  38. Mönkkönen J., Koponen H. M., Ylitalo P. Comparison of the distribution of three bisphosphonates in mice. Pharmacol Toxicol. 1990 Apr;66(4):294–298. doi: 10.1111/j.1600-0773.1990.tb00750.x. [DOI] [PubMed] [Google Scholar]
  39. Mönkkönen J., van Rooijen N., Ylitalo P. Effects of clodronate and pamidronate on splenic and hepatic phagocytic cells of mice. Pharmacol Toxicol. 1991 Apr;68(4):284–286. doi: 10.1111/j.1600-0773.1991.tb01240.x. [DOI] [PubMed] [Google Scholar]
  40. Neese L. W., Standing J. E., Olson E. J., Castro M., Limper A. H. Vitronectin, fibronectin, and gp120 antibody enhance macrophage release of TNF-alpha in response to Pneumocystis carinii. J Immunol. 1994 May 1;152(9):4549–4556. [PubMed] [Google Scholar]
  41. O'Riordan D. M., Standing J. E., Kwon K. Y., Chang D., Crouch E. C., Limper A. H. Surfactant protein D interacts with Pneumocystis carinii and mediates organism adherence to alveolar macrophages. J Clin Invest. 1995 Jun;95(6):2699–2710. doi: 10.1172/JCI117972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. O'Riordan D. M., Standing J. E., Limper A. H. Pneumocystis carinii glycoprotein A binds macrophage mannose receptors. Infect Immun. 1995 Mar;63(3):779–784. doi: 10.1128/iai.63.3.779-784.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pesanti E. L. Interaction of cytokines and alveolar cells with Pneumocystis carinii in vitro. J Infect Dis. 1991 Mar;163(3):611–616. doi: 10.1093/infdis/163.3.611. [DOI] [PubMed] [Google Scholar]
  44. Pesanti E. L., Tomicic T., Donta S. T. Binding of 125I-labelled tumor necrosis factor to Pneumocystis carinii and an insoluble cell wall fraction. J Protozool. 1991 Nov-Dec;38(6):28S–29S. [PubMed] [Google Scholar]
  45. Peters S. G., Prakash U. B. Pneumocystis carinii pneumonia. Review of 53 cases. Am J Med. 1987 Jan;82(1):73–78. doi: 10.1016/0002-9343(87)90380-9. [DOI] [PubMed] [Google Scholar]
  46. Phelps D. S., Rose R. M. Increased recovery of surfactant protein A in AIDS-related pneumonia. Am Rev Respir Dis. 1991 May;143(5 Pt 1):1072–1075. doi: 10.1164/ajrccm/143.5_Pt_1.1072. [DOI] [PubMed] [Google Scholar]
  47. Pottratz S. T., Martin W. J., 2nd Mechanism of Pneumocystis carinii attachment to cultured rat alveolar macrophages. J Clin Invest. 1990 Nov;86(5):1678–1683. doi: 10.1172/JCI114891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Radding J. A., Armstrong M. Y., Ullu E., Richards F. F. Identification and isolation of a major cell surface glycoprotein of Pneumocystis carinii. Infect Immun. 1989 Jul;57(7):2149–2157. doi: 10.1128/iai.57.7.2149-2157.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sepkowitz K. A., Brown A. E., Telzak E. E., Gottlieb S., Armstrong D. Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital. JAMA. 1992 Feb 12;267(6):832–837. [PubMed] [Google Scholar]
  50. Shellito J., Suzara V. V., Blumenfeld W., Beck J. M., Steger H. J., Ermak T. H. A new model of Pneumocystis carinii infection in mice selectively depleted of helper T lymphocytes. J Clin Invest. 1990 May;85(5):1686–1693. doi: 10.1172/JCI114621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Siminski J., Kidd P., Phillips G. D., Collins C., Raghu G. Reversed helper/suppressor T-lymphocyte ratio in bronchoalveolar lavage fluid from patients with breast cancer and Pneumocystis carinii pneumonia. Am Rev Respir Dis. 1991 Feb;143(2):437–440. doi: 10.1164/ajrccm/143.2.437. [DOI] [PubMed] [Google Scholar]
  52. Stringer S. L., Garbe T., Sunkin S. M., Stringer J. R. Genes encoding antigenic surface glycoproteins in Pneumocystis from humans. J Eukaryot Microbiol. 1993 Nov-Dec;40(6):821–826. doi: 10.1111/j.1550-7408.1993.tb04481.x. [DOI] [PubMed] [Google Scholar]
  53. Theus S. A., Linke M. J., Andrews R. P., Walzer P. D. Proliferative and cytokine responses to a major surface glycoprotein of Pneumocystis carinii. Infect Immun. 1993 Nov;61(11):4703–4709. doi: 10.1128/iai.61.11.4703-4709.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Van Rooijen N. The liposome-mediated macrophage 'suicide' technique. J Immunol Methods. 1989 Nov 13;124(1):1–6. doi: 10.1016/0022-1759(89)90178-6. [DOI] [PubMed] [Google Scholar]
  55. Von Behren L. A., Pesanti E. L. Uptake and degradation of Pneumocystis carinii by macrophages in vitro. Am Rev Respir Dis. 1978 Dec;118(6):1051–1059. doi: 10.1164/arrd.1978.118.6.1051. [DOI] [PubMed] [Google Scholar]
  56. Walzer P. D., LaBine M., Redington T. J., Cushion M. T. Lymphocyte changes during chronic administration of and withdrawal from corticosteroids: relation to Pneumocystis carinii pneumonia. J Immunol. 1984 Nov;133(5):2502–2508. [PubMed] [Google Scholar]
  57. Williams M. D., Wright J. R., March K. L., Martin W. J., 2nd Human surfactant protein A enhances attachment of Pneumocystis carinii to rat alveolar macrophages. Am J Respir Cell Mol Biol. 1996 Mar;14(3):232–238. doi: 10.1165/ajrcmb.14.3.8845173. [DOI] [PubMed] [Google Scholar]
  58. Yale S. H., Limper A. H. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc. 1996 Jan;71(1):5–13. doi: 10.4065/71.1.5. [DOI] [PubMed] [Google Scholar]
  59. Zimmerman P. E., Voelker D. R., McCormack F. X., Paulsrud J. R., Martin W. J., 2nd 120-kD surface glycoprotein of Pneumocystis carinii is a ligand for surfactant protein A. J Clin Invest. 1992 Jan;89(1):143–149. doi: 10.1172/JCI115554. [DOI] [PMC free article] [PubMed] [Google Scholar]

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