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. 2001 Feb;102(2):248-53.
doi: 10.1046/j.1365-2567.2001.01161.x.

Pentoxifylline treatment of mice with chronic pulmonary tuberculosis accelerates the development of destructive pathology

J Turner  1 , A A Frank, J V Brooks, P M Marietta, I M Orme
Affiliations

Pentoxifylline treatment of mice with chronic pulmonary tuberculosis accelerates the development of destructive pathology

J Turner et al. Immunology. 2001 Feb.

Abstract

It is well established in animal models that production of the cytokine tumour necrosis factor-alpha (TNF-alpha) is essential to the proper expression of acquired specific resistance following infection with Mycobacterium tuberculosis. This gives rise to an apparent state of chronic disease which over the next 100-200 days is characterized by slowly worsening pathological changes in the lung. To determine whether continued TNF-alpha production was harmful during this phase mice were treated with a TNF-alpha inhibitor, pentoxifylline. It was observed that although this therapy did not alter the numbers of bacteria recovered from the lungs of the infected mice, tissue damage within the lung was accelerated. These data thus demonstrate that production of TNF-alpha, already known to be important during the early expression of resistance to tuberculosis, remains important and beneficial during the chronic stage of the disease.

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Figures

Figure 1
Figure 1
Progression of M. tuberculosis infection in mice treated with pentoxifylline. Mice were infected by aerosol exposure with 102 M. tuberculosis and the course of the infection was followed over time in the lung (a) and spleen (b). Mice receiving pentoxifylline (•) were compared to a control group which had not received the drug (○). Data are expressed as the mean value from four individual mice, ± SEM. Arrows depict initiation of pentoxifylline treatment.
Figure 2
Figure 2
Expression of TNF-α message in the lungs of M. tuberculosis-infected mice. Lung lobes were collected from individual mice at several time-points throughout the study. Total RNA was isolated, transcribed, and probed using primers specific for HPRT and TNF. Messenger RNA from the lungs of four individual wild-type mice (a), or four individual mice which had received pentoxifylline (b), are shown at either 150 or 220 days postinfection.
Figure 3
Figure 3
Expression of MCP-1 and IFN-γ message in the lungs of M. tuberculosis-infected mice. Lung lobes were collected from individual mice at several time-points throughout the study. Total RNA was isolated, transcribed, and probed using primers specific for HPRT, MCP-1 and IFN-γ. Messenger RNA from the lungs of three individual wild-type mice (a), or three individual mice which had received pentoxifylline (b), are shown at either 150 or 220 days postinfection.
Figure 4
Figure 4
Cellular changes within the lung of M. tuberculosis-infected mice. Representative tissue from control mice, or mice receiving pentoxifylline, are depicted. Lesions in wild-type mice consisted of both lymphocyte aggregates associated with foamy macrophages after 150 days of M. tuberculosis infection (a). As the infection progressed, the lesions became more degenerative with aggregates of foamy macrophages associated with lymphocyte foci (b, 200 days). After 250 days of M. tuberculosis, the lesions again presented with lymphocyte foci associated with foamy macrophages (c). The lung lesions of mice receiving pentoxifylline had fewer lymphocyte foci throughout the duration of the experiment, although lymphocytes were scattered within the rafts of foamy macrophages (d, 150 days). As the infection progressed, there was evidence of markedly more macrophage degeneration (e, 200 days) which was associated with regions of necrotic cellular debris associated with cholesterol deposition (f, 250 days). Magnification ×200, size bar = 100 µm. Black arrows depict foamy macrophages; grey arrows show necrotic cellular debris and cholesterol deposition.
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