Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1984 Aug;74(2):460–469. doi: 10.1172/JCI111443

Alveolar macrophage replication. One mechanism for the expansion of the mononuclear phagocyte population in the chronically inflamed lung.

P B Bitterman, L E Saltzman, S Adelberg, V J Ferrans, R G Crystal
PMCID: PMC370498  PMID: 6746904

Abstract

Within any chronically inflamed tissue, there is an increased number of macrophages, pluripotential phagocytic cells that, while critical to host defenses, are also able to profoundly damage parenchymal structure and function. Because of their central role in the inflammatory response, considerable attention has been focused on the mechanisms resulting in an expansion of the macrophage population within an inflamed tissue. Although recruitment of precursor monocytes from the circulation into inflamed tissues clearly plays an important role in macrophage accumulation, it is also possible that replication of tissue macrophages contributes to the expansion of macrophage numbers in inflammation. Because of the accessibility of tissue macrophages with the technique of bronchoalveolar lavage, the lung provides an ideal opportunity to test this hypothesis in humans. To accomplish this, bronchoalveolar lavage was performed to obtain alveolar macrophages from normals (n = 5) and individuals with chronic lung inflammation (normal smokers [n = 5], idiopathic pulmonary fibrosis [n = 13], sarcoidosis [n = 18], and other chronic interstitial lung disorders [n = 11]). Alveolar macrophage replication was quantified by three independent methods: (a) DNA synthesis, assessed by autoradiographic analysis of macrophages cultured for 16 h in the presence of [3H]thymidine; (b) DNA content, assessed by flow cytometric analysis of macrophages fixed immediately after recovery from the lower respiratory tract; and (c) cell division, assessed by cluster formation in semisolid medium. While the proportion of replicating macrophages in normals was very low, there was a 2- to 15-fold increase in this proportion in patients with chronic lung inflammation. In addition, morphologic evaluation demonstrated that individuals with chronic lung inflammation had alveolar macrophages undergoing mitosis. These results suggest that local tissue macrophage replication may play a role in the expansion of the macrophage population in chronic inflammation.

Full text

PDF
460

Images in this article

463Image
on p.463
465Image
on p.465
465Image
on p.465
465Image
on p.465

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. AUERBACH O., STOUT A. P., HAMMOND E. C., GARFINKEL L. SMOKING HABITS AND AGE IN RELATION TO PULMONARY CHANGES. RUPTURE OF ALVEOLAR SEPTUMS, FIBROSIS AND THICKENING OF WALLS OF SMALL ARTERIES AND ARTERIOLES. N Engl J Med. 1963 Nov 14;269:1045–1054. doi: 10.1056/NEJM196311142692001. [DOI] [PubMed] [Google Scholar]
  2. Adamson I. Y., Bowden D. H. Chemotactic and mitogenic components of the alveolar macrophage response to particles ad neutrophil chemoattractant. Am J Pathol. 1982 Oct;109(1):71–77. [PMC free article] [PubMed] [Google Scholar]
  3. Basset F., Corrin B., Spencer H., Lacronique J., Roth C., Soler P., Battesti J. P., Georges R., Chrétien J. Pulmonary histiocytosis X. Am Rev Respir Dis. 1978 Nov;118(5):811–820. doi: 10.1164/arrd.1978.118.5.811. [DOI] [PubMed] [Google Scholar]
  4. Becklake M. R. Asbestos-related diseases of the lungs and pleura: current clinical issues. Am Rev Respir Dis. 1982 Aug;126(2):187–194. doi: 10.1164/arrd.1982.126.2.187. [DOI] [PubMed] [Google Scholar]
  5. Bitterman P. B., Rennard S. I., Adelberg S., Crystal R. G. Role of fibronectin as a growth factor for fibroblasts. J Cell Biol. 1983 Dec;97(6):1925–1932. doi: 10.1083/jcb.97.6.1925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bitterman P. B., Rennard S. I., Hunninghake G. W., Crystal R. G. Human alveolar macrophage growth factor for fibroblasts. Regulation and partial characterization. J Clin Invest. 1982 Oct;70(4):806–822. doi: 10.1172/JCI110677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Blussé van Oud Alblas A., van der Linden-Schrever B., Van Furth R. Origin and kinetics of pulmonary macrophages during an inflammatory reaction induced by intra-alveolar administration of aerosolized heat-killed BCG. Am Rev Respir Dis. 1983 Aug;128(2):276–281. doi: 10.1164/arrd.1983.128.2.276. [DOI] [PubMed] [Google Scholar]
  8. Burgess A. W., Metcalf D. The nature and action of granulocyte-macrophage colony stimulating factors. Blood. 1980 Dec;56(6):947–958. [PubMed] [Google Scholar]
  9. Burgess A. W., Metcalf D. The nature and action of granulocyte-macrophage colony stimulating factors. Blood. 1980 Dec;56(6):947–958. [PubMed] [Google Scholar]
  10. Carrington C. B. Structure and function in sarcoidosis. Ann N Y Acad Sci. 1976;278:265–283. doi: 10.1111/j.1749-6632.1976.tb47038.x. [DOI] [PubMed] [Google Scholar]
  11. Crapo J. D., Barry B. E., Gehr P., Bachofen M., Weibel E. R. Cell number and cell characteristics of the normal human lung. Am Rev Respir Dis. 1982 Jun;125(6):740–745. doi: 10.1164/arrd.1982.125.6.740. [DOI] [PubMed] [Google Scholar]
  12. Crapo J. D., Peters-Golden M., Marsh-Salin J., Shelburne J. S. Pathologic changes in the lungs of oxygen-adapted rats: a morphometric analysis. Lab Invest. 1978 Dec;39(6):640–653. [PubMed] [Google Scholar]
  13. Crissman H. A., Tobey R. A. Cell-cycle analysis in 20 minutes. Science. 1974 Jun 21;184(4143):1297–1298. doi: 10.1126/science.184.4143.1297. [DOI] [PubMed] [Google Scholar]
  14. Crystal R. G., Bitterman P. B., Rennard S. I., Hance A. J., Keogh B. A. Interstitial lung diseases of unknown cause. Disorders characterized by chronic inflammation of the lower respiratory tract. N Engl J Med. 1984 Jan 26;310(4):235–244. doi: 10.1056/NEJM198401263100406. [DOI] [PubMed] [Google Scholar]
  15. Crystal R. G., Fulmer J. D., Roberts W. C., Moss M. L., Line B. R., Reynolds H. Y. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med. 1976 Dec;85(6):769–788. doi: 10.7326/0003-4819-85-6-769. [DOI] [PubMed] [Google Scholar]
  16. DeLustro F., Sherer G. K., LeRoy E. C. Human monocyte stimulation of fibroblast growth by a soluble mediator(s). J Reticuloendothel Soc. 1980 Dec;28(6):519–532. [PubMed] [Google Scholar]
  17. Duncan M. R., Sadlik J. R., Hadden J. W. Glucocorticoid modulation of lymphokine-induced macrophage proliferation. Cell Immunol. 1982 Feb;67(1):23–36. doi: 10.1016/0008-8749(82)90196-4. [DOI] [PubMed] [Google Scholar]
  18. EDWARDS J. L., KOCH A. PARENCHYMAL AND LITTORAL CELL PROLIFERATION DURING LIVER REGENERATION. Lab Invest. 1964 Jan;13:32–43. [PubMed] [Google Scholar]
  19. Evans M. J., Bils R. F. Identification of cells labeled with tritiated thymidine in the pulmonary alveolar walls of the mouse. Am Rev Respir Dis. 1969 Sep;100(3):372–378. doi: 10.1164/arrd.1969.100.3.372. [DOI] [PubMed] [Google Scholar]
  20. Golde D. W., Byers L. A., Finley T. N. Proliferative capacity of human alveolar macrophage. Nature. 1974 Feb 8;247(5440):373–375. doi: 10.1038/247373a0. [DOI] [PubMed] [Google Scholar]
  21. Hayatdavoudi G., O'Neil J. J., Barry B. E., Freeman B. A., Crapo J. D. Pulmonary injury in rats following continuous exposure to 60% O2 for 7 days. J Appl Physiol Respir Environ Exerc Physiol. 1981 Nov;51(5):1220–1231. doi: 10.1152/jappl.1981.51.5.1220. [DOI] [PubMed] [Google Scholar]
  22. Hoidal J. R., Beall G. D., Repine J. E. Production of hydroxyl radical by human alveolar macrophages. Infect Immun. 1979 Dec;26(3):1088–1092. doi: 10.1128/iai.26.3.1088-1092.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hoidal J. R., Fox R. B., LeMarbe P. A., Perri R., Repine J. E. Altered oxidative metabolic responses in vitro of alveolar macrophages from asymptomatic cigarette smokers. Am Rev Respir Dis. 1981 Jan;123(1):85–89. doi: 10.1164/arrd.1981.123.1.85. [DOI] [PubMed] [Google Scholar]
  24. Hunninghake G. W., Crystal R. G. Cigarette smoking and lung destruction. Accumulation of neutrophils in the lungs of cigarette smokers. Am Rev Respir Dis. 1983 Nov;128(5):833–838. doi: 10.1164/arrd.1983.128.5.833. [DOI] [PubMed] [Google Scholar]
  25. Hunninghake G. W., Gadek J. E., Fales H. M., Crystal R. G. Human alveolar macrophage-derived chemotactic factor for neutrophils. Stimuli and partial characterization. J Clin Invest. 1980 Sep;66(3):473–483. doi: 10.1172/JCI109878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hunninghake G. W., Gadek J. E., Kawanami O., Ferrans V. J., Crystal R. G. Inflammatory and immune processes in the human lung in health and disease: evaluation by bronchoalveolar lavage. Am J Pathol. 1979 Oct;97(1):149–206. [PMC free article] [PubMed] [Google Scholar]
  27. Hunninghake G. W., Gadek J. E., Szapiel S. V., Strumpf I. J., Kawanami O., Ferrans V. J., Keogh B. A., Crystal R. G. The human alveolar macrophage. Methods Cell Biol. 1980;21A:95–105. doi: 10.1016/s0091-679x(08)60760-8. [DOI] [PubMed] [Google Scholar]
  28. Hunninghake G. W., Gadek J. E., Young R. C., Jr, Kawanami O., Ferrans V. J., Crystal R. G. Maintenance of granuloma formation in pulmonary sarcoidosis by T lymphocytes within the lung. N Engl J Med. 1980 Mar 13;302(11):594–598. doi: 10.1056/NEJM198003133021102. [DOI] [PubMed] [Google Scholar]
  29. Johnston R. B., Jr, Godzik C. A., Cohn Z. A. Increased superoxide anion production by immunologically activated and chemically elicited macrophages. J Exp Med. 1978 Jul 1;148(1):115–127. doi: 10.1084/jem.148.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kawanami O., Ferrans V. J., Roberts W. C., Crystal R. G., Fulmer J. D. Anchoring fibrils. A new connective tissue structure in fibrotic lung disease. Am J Pathol. 1978 Aug;92(2):389–410. [PMC free article] [PubMed] [Google Scholar]
  31. Leibovich S. J., Ross R. A macrophage-dependent factor that stimulates the proliferation of fibroblasts in vitro. Am J Pathol. 1976 Sep;84(3):501–514. [PMC free article] [PubMed] [Google Scholar]
  32. Lin H. S., Kuhn C., Kuo T. Clonal growth of hamster free alveolar cells in soft agar. J Exp Med. 1975 Oct 1;142(4):877–886. doi: 10.1084/jem.142.4.877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lin H. S., Stewart C. C. Peritoneal exudate cells. I. Growth requirement of cells capable of forming colonies in soft agar. J Cell Physiol. 1974 Jun;83(3):369–378. doi: 10.1002/jcp.1040830307. [DOI] [PubMed] [Google Scholar]
  34. MACKANESS G. B. Cellular resistance to infection. J Exp Med. 1962 Sep 1;116:381–406. doi: 10.1084/jem.116.3.381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. McGuire R. L., Babiuk L. A. In vitro culture characteristics of bovine alveolar macrophages. J Reticuloendothel Soc. 1982 Mar;31(3):251–260. [PubMed] [Google Scholar]
  36. Metcalf D. Studies on colony formation in vitro by mouse bone marrow cells. II. Action of colony stimulating factor. J Cell Physiol. 1970 Aug;76(1):89–99. doi: 10.1002/jcp.1040760113. [DOI] [PubMed] [Google Scholar]
  37. Meuret G., Schildknecht O., Joder P., Senn H. Proliferation activity and bacteriostatic potential of human blood monocytes, macrophages in pleural effusions, ascites, and of alveolar macrophages. Blut. 1980 Jan;40(1):17–25. doi: 10.1007/BF01028360. [DOI] [PubMed] [Google Scholar]
  38. Neumann C., Sorg C. Regulation of plasminogen activator secretion, interferon induction and proliferation in murine macrophages. Eur J Immunol. 1983 Feb;13(2):143–147. doi: 10.1002/eji.1830130210. [DOI] [PubMed] [Google Scholar]
  39. Rennard S. I., Hunninghake G. W., Bitterman P. B., Crystal R. G. Production of fibronectin by the human alveolar macrophage: mechanism for the recruitment of fibroblasts to sites of tissue injury in interstitial lung diseases. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7147–7151. doi: 10.1073/pnas.78.11.7147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Salahuddin S. Z., Markham P. D., Gallo R. C. Establishment of long-term monocyte suspension cultures from normal human peripheral blood. J Exp Med. 1982 Jun 1;155(6):1842–1857. doi: 10.1084/jem.155.6.1842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Scadding J. G., Hinson K. F. Diffuse fibrosing alveolitis (diffuse interstitial fibrosis of the lungs). Correlation of histology at biopsy with prognosis. Thorax. 1967 Jul;22(4):291–304. doi: 10.1136/thx.22.4.291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Schmidt J. A., Mizel S. B., Cohen D., Green I. Interleukin 1, a potential regulator of fibroblast proliferation. J Immunol. 1982 May;128(5):2177–2182. [PubMed] [Google Scholar]
  43. Soderland S. C., Naum Y. Letter: Growth of pulmonary alveolar macrophages in vitro. Nature. 1973 Sep 21;245(5421):150–152. doi: 10.1038/245150a0. [DOI] [PubMed] [Google Scholar]
  44. Spencer H. Interstitial pneumonia. Annu Rev Med. 1967;18:423–442. doi: 10.1146/annurev.me.18.020167.002231. [DOI] [PubMed] [Google Scholar]
  45. Thomas E. D., Ramberg R. E., Sale G. E., Sparkes R. S., Golde D. W. Direct evidence for a bone marrow origin of the alveolar macrophage in man. Science. 1976 Jun 4;192(4243):1016–1018. doi: 10.1126/science.775638. [DOI] [PubMed] [Google Scholar]
  46. Valdivia E., Hensley G., Leory E. P., Wu J., Jaeschke W. Morphology and pathogenesis of desquamative interstitial pneumonitis. Thorax. 1977 Feb;32(1):7–18. doi: 10.1136/thx.32.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Werb Z. Biochemical actions of glucocorticoids on macrophages in culture. Specific inhibition of elastase, collagenase, and plasminogen activator secretion and effects on other metabolic functions. J Exp Med. 1978 Jun 1;147(6):1695–1712. doi: 10.1084/jem.147.6.1695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Werb Z., Gordon S. Elastase secretion by stimulated macrophages. Characterization and regulation. J Exp Med. 1975 Aug 1;142(2):361–377. doi: 10.1084/jem.142.2.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Werb Z., Gordon S. Secretion of a specific collagenase by stimulated macrophages. J Exp Med. 1975 Aug 1;142(2):346–360. doi: 10.1084/jem.142.2.346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Worton R. G., Duff C. Karyotyping. Methods Enzymol. 1979;58:322–344. doi: 10.1016/s0076-6879(79)58148-8. [DOI] [PubMed] [Google Scholar]
  51. van Furth R., Cohn Z. A. The origin and kinetics of mononuclear phagocytes. J Exp Med. 1968 Sep 1;128(3):415–435. doi: 10.1084/jem.128.3.415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. van der Meer J. W., van de Gevel J. S., Beelen R. H., Fluitsma D., Hoefsmit E. C., van Furth R. Culture of human bone marrow in the teflon culture bag: identification of the human monoblast. J Reticuloendothel Soc. 1982 Nov;32(5):355–369. [PubMed] [Google Scholar]
  53. van oud Alblas A. B., van Furth R. Origin, Kinetics, and characteristics of pulmonary macrophages in the normal steady state. J Exp Med. 1979 Jun 1;149(6):1504–1518. doi: 10.1084/jem.149.6.1504. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES