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. 1996 Nov;64(11):4776–4787. doi: 10.1128/iai.64.11.4776-4787.1996

Cavitary tuberculosis produced in rabbits by aerosolized virulent tubercle bacilli.

P J Converse 1, A M Dannenberg Jr 1, J E Estep 1, K Sugisaki 1, Y Abe 1, B H Schofield 1, M L Pitt 1
PMCID: PMC174445  PMID: 8890239

Abstract

Liquefaction of solid caseous tuberculous lesions and the subsequent cavity formation are probably the most dangerous processes in the pathogenesis of human pulmonary tuberculosis. In liquefied caseum, the tubercle bacilli grow extracellularly for the first time since the onset of the disease and can reach such large numbers that mutants with antimicrobial resistance may develop. From a cavity, the bacilli enter the bronchial tree and spread to other parts of the lung and also to other people. Of the commonly used laboratory animals, the rabbit is the only one in which cavitary tuberculosis can be readily produced. This report is the first to describe and analyze the complete course of cavitary tuberculosis, produced by aerosolized virulent bovine-type tubercle bacilli in commercially available New Zealand white rabbits. After the inhalation of 220 to 880 bacillary units, all of the rabbits were overtly well until they were sacrificed at 33 weeks. After the inhalation of 3,900 to 5,800 bacillary units, half of the rabbits died of progressive tuberculosis between 5 and 9 weeks and the other half lived until they were sacrificed at 18 weeks. Pulmonary cavities developed in both low- and high-dose groups, some beginning as early as 6 weeks. Bacilli from primary cavities sometimes caused nearby secondary cavities, but more frequently, they ascended the bronchial escalator, were swallowed, and caused secondary tubercles in the lymphoid tissue of the appendix and ileocecal junction. Histologically, and by culture, the number of bacilli found in the liquefied caseum varied from many to comparatively few. Strong tuberculin reactions at 4 weeks after infection were associated with fewer primary lesions, while strong tuberculin reactions at 33 weeks were associated with more cavitary lesions. In the tuberculous granulation tissue surrounding caseous and liquefied pulmonary foci and cavities, we found many mature epithelioid macrophages that contained high levels of the proteinase cathepsin D. Therefore, cathepsin D probably plays a major role in the liquefaction of solid caseous material and in the subsequent cavity formation.

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Selected References

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  1. Ando M., Dannenberg A. M., Jr, Sugimoto M., Tepper B. S. Histochemical studies relating the activation of macrophages to the intracellular destruction of tubercle bacilli. Am J Pathol. 1977 Mar;86(3):623–634. [PMC free article] [PubMed] [Google Scholar]
  2. Beynen A. C., Meijer G. W., Lemmens A. G., Glatz J. F., Versluis A., Katan M. B., Van Zutphen L. F. Sterol balance and cholesterol absorption in inbred strains of rabbits hypo- or hyperresponsive to dietary cholesterol. Atherosclerosis. 1989 Jun;77(2-3):151–157. doi: 10.1016/0021-9150(89)90076-2. [DOI] [PubMed] [Google Scholar]
  3. COWN W. B., KETHLEY T. W., FINCHER E. L. The critical-orifice liquid impinger as a sampler for bacterial aerosols. Appl Microbiol. 1957 Mar;5(2):119–124. doi: 10.1128/am.5.2.119-124.1957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cohn Z. A., Benson B. The in vitro differentiation of mononuclear phagocytes. 3. The reversibility of granule and hydrolytic enzyme formation and the turnover of granule constituents. J Exp Med. 1965 Sep 1;122(3):455–466. doi: 10.1084/jem.122.3.455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dannenberg A. M., Jr, Ando M., Shima K. Macrophage accumulation, division, maturation, and digestive and microbicidal capacities in tuberculous lesions. 3. The turnover of macrophages and its relation to their activation and antimicrobial immunity in primary BCG lesions and those of reinfection. J Immunol. 1972 Nov;109(5):1109–1121. [PubMed] [Google Scholar]
  6. Dannenberg A. M., Jr Cellular hypersensitivity and cellular immunity in the pathogensis of tuberculosis: specificity, systemic and local nature, and associated macrophage enzymes. Bacteriol Rev. 1968 Jun;32(2):85–102. doi: 10.1128/br.32.2.85-102.1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dannenberg A. M., Jr Delayed-type hypersensitivity and cell-mediated immunity in the pathogenesis of tuberculosis. Immunol Today. 1991 Jul;12(7):228–233. doi: 10.1016/0167-5699(91)90035-R. [DOI] [PubMed] [Google Scholar]
  8. Dannenberg A. M., Jr Immunopathogenesis of pulmonary tuberculosis. Hosp Pract (Off Ed) 1993 Jan 15;28(1):51–58. doi: 10.1080/21548331.1993.11442738. [DOI] [PubMed] [Google Scholar]
  9. Dannenberg A. M., Jr, Meyer O. T., Esterly J. R., Kambara T. The local nature of immunity in tuberculosis, illustrated histochemically in dermal BCG lesions. J Immunol. 1968 May;100(5):931–941. [PubMed] [Google Scholar]
  10. Dannenberg A. M., Jr, Sugimoto M. Liquefaction of caseous foci in tuberculosis. Am Rev Respir Dis. 1976 Mar;113(3):257–259. doi: 10.1164/arrd.1976.113.3.257. [DOI] [PubMed] [Google Scholar]
  11. Lurie M. B., Dannenberg A. M. Macrophage Function in Infectious Disease with Inbred Rabbits. Bacteriol Rev. 1965 Dec;29(4):466–476. doi: 10.1128/br.29.4.466-476.1965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. McMurray D. N., Bartow R. A. Immunosuppression and alteration of resistance to pulmonary tuberculosis in guinea pigs by protein undernutrition. J Nutr. 1992 Mar;122(3 Suppl):738–743. doi: 10.1093/jn/122.suppl_3.738. [DOI] [PubMed] [Google Scholar]
  13. Meijer G. W., Stalenhoef A. F., Demacker P. N., Mol M. J., Van Zutphen L. F., Beynen A. C. Low-density lipoprotein turnover in inbred strains of rabbits hypo- or hyperresponsive to dietary cholesterol. Lipids. 1992 Jun;27(6):474–477. doi: 10.1007/BF02536392. [DOI] [PubMed] [Google Scholar]
  14. Meijer G. W., Van der Palen J. G., Geelen M. J., Versluis A., Van Zutphen L. F., Beynen A. C. Secretion of lipoprotein cholesterol by perfused livers from rabbits hypo- or hyperresponsive to dietary cholesterol: greater dietary cholesterol-induced secretion in hyperresponsive rabbits. J Nutr. 1992 May;122(5):1164–1173. doi: 10.1093/jn/122.5.1164. [DOI] [PubMed] [Google Scholar]
  15. Namba M., Dannenberg A. M., Jr, Tanaka F. Improvement in the histochemical demonstration of acid phosphatase, beta-galactosidase and nonspecific esterase in glycol methacrylate tissue sections by cold temperature embedding. Stain Technol. 1983 Jul;58(4):207–213. doi: 10.3109/10520298309066786. [DOI] [PubMed] [Google Scholar]
  16. Rojas-Espinosa O., Dannenberg A. M., Jr, Sternberger L. A., Tsuda T. The role of cathepsin D in the pathogenesis of tuberculosis. A histochemical study employing unlabeled antibodies and the peroxidase-antiperoxidase complex. Am J Pathol. 1974 Jan;74(1):1–17. [PMC free article] [PubMed] [Google Scholar]
  17. Simon R. H., Paine R., 3rd Participation of pulmonary alveolar epithelial cells in lung inflammation. J Lab Clin Med. 1995 Aug;126(2):108–118. [PubMed] [Google Scholar]
  18. Suga M., Dannenberg A. M., Jr, Higuchi S. Macrophage functional heterogeneity in vivo. Macrolocal and microlocal macrophage activation, identified by double-staining tissue sections of BCG granulomas for pairs of enzymes. Am J Pathol. 1980 May;99(2):305–323. [PMC free article] [PubMed] [Google Scholar]
  19. Tsuda T., Dannenberg A. M., Jr, Ando M., Rojas-Espinosa O., Shima K. Enzymes in tuberculous lesions hydrolyzing protein, hyaluronic acid and chondroitin sulfate: a study of isolated macrophages and developing and healing rabbit BCG lesions with substrate film techniques; the shift of enzyme pH optima towards neutrality in "intact" cells and tissues. J Reticuloendothel Soc. 1974 Oct;16(4):220–231. [PubMed] [Google Scholar]
  20. Vogt R. F., Jr, Hynes N. A., Dannenberg A. M., Jr, Castracane S., Weiss L. Improved techniques using Giemsa stained glycol methacrylate tissue sections to quantitate basophils and other leukocytes in inflammatory skin lesions. Stain Technol. 1983 Jul;58(4):193–205. doi: 10.3109/10520298309066785. [DOI] [PubMed] [Google Scholar]
  21. Wilhelmsen C. L., Pitt M. L. Lesions of acute inhaled lethal ricin intoxication in rhesus monkeys. Vet Pathol. 1996 May;33(3):296–302. doi: 10.1177/030098589603300306. [DOI] [PubMed] [Google Scholar]
  22. YAMORI T. ON PHAGOCYTES: THEIR STRUCTURES AND PARTICIPATION IN INFLAMMATION. Acta Pathol Jpn. 1964 Jan;14:1–43. [PubMed] [Google Scholar]
  23. Yamamura Y., Ogawa Y., Maeda H., Yamamura Y. Prevention of tuberculous cavity formation by desensitization with tuberculin-active peptide. Am Rev Respir Dis. 1974 Jun;109(6):594–601. doi: 10.1164/arrd.1974.109.6.594. [DOI] [PubMed] [Google Scholar]
  24. Yamamura Y., Ogawa Y., Yamagata H., Yamamura Y. Prevention of tuberculous cavity formation by immunosuppressive drugs. Am Rev Respir Dis. 1968 Oct;98(4):720–723. doi: 10.1164/arrd.1968.98.4.720. [DOI] [PubMed] [Google Scholar]

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