Phosphodiesterase-4 Inhibition Combined with Isoniazid Treatment of Rabbits with Pulmonary Tuberculosis Reduces Macrophage Activation and Lung Pathology

Abstract

Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-␣ and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment. Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading infectious disease causes of morbidity and mortality worldwide. Although current multidrug regimens are generally effective, treatment is lengthy, requiring a minimum of 6 months and sometimes more than 1 year, for patients with drug-resistant TB or other clinical complications.1 Even after successful microbiological cure, pulmonary TB patients are often left with residual lung damage.2-5 Pulmonary impairment after TB treatment has been observed as changes in the structure and function of bronchial parenchymal tissue and the persistence of fibrocavitary lung damage.6,7 The risk and the extent of chronic respiratory dysfunction in individuals after curative therapy have been shown to increase with the number of previous TB episodes. 8 Most importantly, one recent study in South Africa found a fourfold higher risk of TB due to reinfection in previously treated patients compared with incidence rates among new TB cases.

Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases

“…More recently, the Kaplan group has reported on MMP activity in the rabbit model. Expression of the collagenases (MMP-1, -13, and -14), gelatinases (MMP-2 and -9), stromelysin (MMP-3), and elastase (MMP-12) was up-regulated in the lungs of TB-infected rabbits with destructive pathology, which was consistent with a role for MMPs in TB immunopathogenesis (49). There are also emerging data that MMP-1 is enzymatically active and predominantly increased in the wall of TB cavities compared with granulomatous tissues (11).…”

Lentinula edodes β-glucan enriched diet induces pro- and anti-inflammatory macrophages in rabbit

“…GAPDH expression was included as housekeeping gene using primers described previously [20]. GAPDH Ct values were subtracted from the Ct values obtained for each marker molecule in order to obtain the ΔCt used for comparisons.…”

The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells

“…Measuring drug levels by (LC–MS/MS) is invasive and therefore requires the use of animal models to mimic the pathology of human TB and the ability to generate lesions that are large enough to enable accurate dissection and measurements. The rabbit model meets these criteria 35, 36 and has therefore been increasingly used in pharmacological studies 11, 37, 38 . Following the administration of single drugs or drug combinations, population pharmacokinetic modelling enables the rate and extent of drug distribution to be calculated.…”