Experimental murine mycobacteriosis: evaluation of the functional activity of alveolar macrophages in thalidomide- treated mice

Abstract

Thalidomide is a selective inhibitor of tumor necrosis factor-α (TNF-α), a cytokine involved in mycobacterial death mechanisms. We investigated the role of this drug in the functional activity of alveolar macrophages in the presence of infection induced by intranasal inoculation of Mycobacterium avium in thalidomide-treated and untreated adult Swiss mice. Sixty animals were inoculated with 5 x 10 6 M. avium by the respiratory route. Thirty animals received daily thalidomide (30 mg/kg mouse) and 30 received water by gavage up to sacrifice. Ten non-inoculated mice were used as a control group. Lots of animals from each group were evaluated until 6 weeks after inoculation. Infection resulted in an increased total number of inflammatory cells as well as increased activity of pulmonary macrophages. Histologically, intranasal inoculation of bacilli resulted in small mononuclear infiltrates located at the periphery of the organ. Culture of lung fragments revealed the presence of bacilli only at the beginning and at the end of the experimental period. Thalidomide administration did not affect the microbiological or histological features of the infection. Thalidomide-treated and untreated animals showed the same amount of M. avium colonies 3 weeks after infection. Although it did not affect bacillary clearance, thalidomide administration resulted in a decreased percent of spread cells and release of hydrogen peroxide, suggesting that factors other than TNF-α play a role in the killing of mycobacteria by alveolar macrophages. Thalidomide administration also reduced the number of spread cells among resident macrophages, suggesting a direct effect of the drug on this phenomenon.

Thalidomide treatment modulates macrophage pro-inflammatory function and cytokine levels in Klebsiella pneumoniae B5055 induced pneumonia in BALB/c mice

“…However, thalidomide treatment in this study resulted in decreased production of H 2 O 2 by lung alveolar macrophages and thus protected the host from tissue damage due to increased lipid peroxidation. Similar findings were also reported by Arruda et al who showed inhibition of both macrophage spreading and H 2 O 2 release following thalidomide treatment during the course of experimental mycobacteriosis [19]. Thus, macrophage spreading and H 2 O 2 release are linked processes and inhibition of one can also limit the activity of other.…”

“…In the present study, acute lung infection with K. pneumoniae B5055 in mice resulted in spreading of lung alveolar macrophages, indicating highly active macrophages with increased tissue damaging potential, whereas a decrease in spreading character was observed with thalidomide treatment. Similar observation was made by Arruda et al [19], while investigating immunomodulatory potential of thalidomide in experimental murine mycobacteriosis. Macrophage spreading involves protein kinase C (PKC) dependent intracellular signaling pathway.…”

“…Alveolar macrophages were evaluated in terms of macrophage spreading ability by following the method described by Rabinovitch et al [18] and Arruda et al [19]. Cell suspensions containing about 70% macrophages were layered on glass cover slips for 10 min at 22°C.…”

Assessment of TNFα contribution to the functional up-regulation of kinin B1 receptors in the mouse paw after treatment with LPS

“…The edema was evoked by the s.c. injection of des-Arg 9 -BK (50 nmol/paw). The doses of the anti-TNFa antibody and thalidomide were selected on the basis of literature data or pilot experiments [16][17][18].…”

Effects of combined therapy with thalidomide and glucantime on leishmaniasis induced by Leishmania major in BALB/c mice

“…Thalidomide administration reduced the number of spread cells among resident macrophages in experimental murine tuberculosis (Arruda et al, 2004). In addition, thalidomide is now being considered as an adjuvant treatment for tuberculosis since it affects cytokine production and T lymphocyte proliferation.…”