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The American Journal of Pathology logoLink to The American Journal of Pathology
. 1993 Oct;143(4):1189–1199.

Macrophage production of basic fibroblast growth factor in the fibroproliferative disorder of alveolar fibrosis after lung injury.

C Henke 1, W Marineili 1, J Jessurun 1, J Fox 1, D Harms 1, M Peterson 1, L Chiang 1, P Doran 1
PMCID: PMC1887071  PMID: 7692734

Abstract

In organ repair following injury, macrophages accumulate and granulation tissue, comprised of fibroblasts and endothelial cells, develops in the injured area. Basic fibroblast growth factor (bFGF), a potent stimulator of fibroblast and endothelial cell growth, has been linked to the fibroproliferative process. Macrophages are thought to play a central role in the fibroproliferative response, and prior studies indicate that they produce bFGF. Whereas it is plausible that macrophages produce bFGF in a fibroproliferative process, currently no data exists that directly identifies the macrophage as a source of bFGF in a fibroproliferative disorder. We used the model of acute intraalveolar granulation tissue formation following lung injury to determine if the macrophage was a cellular source of bFGF in a naturally occurring fibroproliferative process. To examine this hypothesis, patients with severe acute lung injury underwent bronchoalveolar lavage during the phase of lung repair. Polymerase chain reaction and Northern analysis of macrophage RNA revealed the presence of two species of bFGF messenger RNA (4.4 kb and 1.9 kb). Metabolic labeling studies of recovered macrophages revealed a newly synthesized 18-kd protein with antigenic similarity to bFGF. Immunohistochemical evaluation of lung tissue from patients who died following acute lung injury, showed numerous bFGF immunoreactive macrophages present within airspaces containing fibroblastic and vascular tissue proliferation. This investigation has identified the alveolar macrophage as a cellular source of bFGF in the fibroproliferative disorder of intraalveolar fibrosis following acute lung injury.

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Selected References

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  1. Abraham J. A., Mergia A., Whang J. L., Tumolo A., Friedman J., Hjerrild K. A., Gospodarowicz D., Fiddes J. C. Nucleotide sequence of a bovine clone encoding the angiogenic protein, basic fibroblast growth factor. Science. 1986 Aug 1;233(4763):545–548. doi: 10.1126/science.2425435. [DOI] [PubMed] [Google Scholar]
  2. Abraham J. A., Whang J. L., Tumolo A., Mergia A., Friedman J., Gospodarowicz D., Fiddes J. C. Human basic fibroblast growth factor: nucleotide sequence and genomic organization. EMBO J. 1986 Oct;5(10):2523–2528. doi: 10.1002/j.1460-2075.1986.tb04530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bachofen M., Weibel E. R. Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med. 1982 Jan;3(1):35–56. [PubMed] [Google Scholar]
  4. Baird A., Mormède P., Böhlen P. Immunoreactive fibroblast growth factor in cells of peritoneal exudate suggests its identity with macrophage-derived growth factor. Biochem Biophys Res Commun. 1985 Jan 16;126(1):358–364. doi: 10.1016/0006-291x(85)90614-x. [DOI] [PubMed] [Google Scholar]
  5. Broadley K. N., Aquino A. M., Woodward S. C., Buckley-Sturrock A., Sato Y., Rifkin D. B., Davidson J. M. Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair. Lab Invest. 1989 Nov;61(5):571–575. [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Cordell J. L., Falini B., Erber W. N., Ghosh A. K., Abdulaziz Z., MacDonald S., Pulford K. A., Stein H., Mason D. Y. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem. 1984 Feb;32(2):219–229. doi: 10.1177/32.2.6198355. [DOI] [PubMed] [Google Scholar]
  8. Folkman J., Klagsbrun M., Sasse J., Wadzinski M., Ingber D., Vlodavsky I. A heparin-binding angiogenic protein--basic fibroblast growth factor--is stored within basement membrane. Am J Pathol. 1988 Feb;130(2):393–400. [PMC free article] [PubMed] [Google Scholar]
  9. Fowler A. A., Hyers T. M., Fisher B. J., Bechard D. E., Centor R. M., Webster R. O. The adult respiratory distress syndrome. Cell populations and soluble mediators in the air spaces of patients at high risk. Am Rev Respir Dis. 1987 Nov;136(5):1225–1231. doi: 10.1164/ajrccm/136.5.1225. [DOI] [PubMed] [Google Scholar]
  10. Fukuda Y., Ishizaki M., Masuda Y., Kimura G., Kawanami O., Masugi Y. The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage. Am J Pathol. 1987 Jan;126(1):171–182. [PMC free article] [PubMed] [Google Scholar]
  11. Gonzalez A. M., Buscaglia M., Fox R., Isacchi A., Sarmientos P., Farris J., Ong M., Martineau D., Lappi D. A., Baird A. Basic fibroblast growth factor in Dupuytren's contracture. Am J Pathol. 1992 Sep;141(3):661–671. [PMC free article] [PubMed] [Google Scholar]
  12. Henke C., Fiegel V., Peterson M., Wick M., Knighton D., McCarthy J., Bitterman P. Identification and partial characterization of angiogenesis bioactivity in the lower respiratory tract after acute lung injury. J Clin Invest. 1991 Oct;88(4):1386–1395. doi: 10.1172/JCI115445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kandel J., Bossy-Wetzel E., Radvanyi F., Klagsbrun M., Folkman J., Hanahan D. Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell. 1991 Sep 20;66(6):1095–1104. doi: 10.1016/0092-8674(91)90033-u. [DOI] [PubMed] [Google Scholar]
  14. Knighton D. R., Fiegel V. D. Macrophage-derived growth factors in wound healing: regulation of growth factor production by the oxygen microenvironment. Am Rev Respir Dis. 1989 Oct;140(4):1108–1111. doi: 10.1164/ajrccm/140.4.1108. [DOI] [PubMed] [Google Scholar]
  15. Knighton D. R., Hunt T. K., Scheuenstuhl H., Halliday B. J., Werb Z., Banda M. J. Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science. 1983 Sep 23;221(4617):1283–1285. doi: 10.1126/science.6612342. [DOI] [PubMed] [Google Scholar]
  16. Kurokawa T., Sasada R., Iwane M., Igarashi K. Cloning and expression of cDNA encoding human basic fibroblast growth factor. FEBS Lett. 1987 Mar 9;213(1):189–194. doi: 10.1016/0014-5793(87)81489-8. [DOI] [PubMed] [Google Scholar]
  17. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  18. Leibovich S. J., Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975 Jan;78(1):71–100. [PMC free article] [PubMed] [Google Scholar]
  19. Martin B. M., Gimbrone M. A., Jr, Unanue E. R., Cotran R. S. Stimulation of nonlymphoid mesenchymal cell proliferation by a macrophage-derived growth factor. J Immunol. 1981 Apr;126(4):1510–1515. [PubMed] [Google Scholar]
  20. Matsudaira P. Sequence from picomole quantities of proteins electroblotted onto polyvinylidene difluoride membranes. J Biol Chem. 1987 Jul 25;262(21):10035–10038. [PubMed] [Google Scholar]
  21. McGee G. S., Davidson J. M., Buckley A., Sommer A., Woodward S. C., Aquino A. M., Barbour R., Demetriou A. A. Recombinant basic fibroblast growth factor accelerates wound healing. J Surg Res. 1988 Jul;45(1):145–153. doi: 10.1016/0022-4804(88)90034-0. [DOI] [PubMed] [Google Scholar]
  22. Muthukrishnan L., Warder E., McNeil P. L. Basic fibroblast growth factor is efficiently released from a cytolsolic storage site through plasma membrane disruptions of endothelial cells. J Cell Physiol. 1991 Jul;148(1):1–16. doi: 10.1002/jcp.1041480102. [DOI] [PubMed] [Google Scholar]
  23. Odink K., Cerletti N., Brüggen J., Clerc R. G., Tarcsay L., Zwadlo G., Gerhards G., Schlegel R., Sorg C. Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature. 1987 Nov 5;330(6143):80–82. doi: 10.1038/330080a0. [DOI] [PubMed] [Google Scholar]
  24. Pierce G. F., Tarpley J. E., Yanagihara D., Mustoe T. A., Fox G. M., Thomason A. Platelet-derived growth factor (BB homodimer), transforming growth factor-beta 1, and basic fibroblast growth factor in dermal wound healing. Neovessel and matrix formation and cessation of repair. Am J Pathol. 1992 Jun;140(6):1375–1388. [PMC free article] [PubMed] [Google Scholar]
  25. Polverini P. J., Cotran P. S., Gimbrone M. A., Jr, Unanue E. R. Activated macrophages induce vascular proliferation. Nature. 1977 Oct 27;269(5631):804–806. doi: 10.1038/269804a0. [DOI] [PubMed] [Google Scholar]
  26. Pratt P. C., Vollmer R. T., Shelburne J. D., Crapo J. D. Pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. I. Light microscopy. Am J Pathol. 1979 Apr;95(1):191–214. [PMC free article] [PubMed] [Google Scholar]
  27. Rappolee D. A., Mark D., Banda M. J., Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science. 1988 Aug 5;241(4866):708–712. doi: 10.1126/science.3041594. [DOI] [PubMed] [Google Scholar]
  28. Rifkin D. B., Moscatelli D. Recent developments in the cell biology of basic fibroblast growth factor. J Cell Biol. 1989 Jul;109(1):1–6. doi: 10.1083/jcb.109.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Schulze-Osthoff K., Risau W., Vollmer E., Sorg C. In situ detection of basic fibroblast growth factor by highly specific antibodies. Am J Pathol. 1990 Jul;137(1):85–92. [PMC free article] [PubMed] [Google Scholar]
  30. Shimokado K., Raines E. W., Madtes D. K., Barrett T. B., Benditt E. P., Ross R. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 1985 Nov;43(1):277–286. doi: 10.1016/0092-8674(85)90033-9. [DOI] [PubMed] [Google Scholar]
  31. Snyder L. S., Hertz M. I., Peterson M. S., Harmon K. R., Marinelli W. A., Henke C. A., Greenheck J. R., Chen B., Bitterman P. B. Acute lung injury. Pathogenesis of intraalveolar fibrosis. J Clin Invest. 1991 Aug;88(2):663–673. doi: 10.1172/JCI115351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sporn M. B., Roberts A. B., Wakefield L. M., Assoian R. K. Transforming growth factor-beta: biological function and chemical structure. Science. 1986 Aug 1;233(4763):532–534. doi: 10.1126/science.3487831. [DOI] [PubMed] [Google Scholar]
  33. Thakral K. K., Goodson W. H., 3rd, Hunt T. K. Stimulation of wound blood vessel growth by wound macrophages. J Surg Res. 1979 Apr;26(4):430–436. doi: 10.1016/0022-4804(79)90031-3. [DOI] [PubMed] [Google Scholar]
  34. Vlodavsky I., Folkman J., Sullivan R., Fridman R., Ishai-Michaeli R., Sasse J., Klagsbrun M. Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2292–2296. doi: 10.1073/pnas.84.8.2292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Whitby D. J., Ferguson M. W. Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol. 1991 Sep;147(1):207–215. doi: 10.1016/s0012-1606(05)80018-1. [DOI] [PubMed] [Google Scholar]

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