The proinflammatory cytokine IL-18 was investigated for its role in human myocardial function. An ischemia͞reperfusion (I͞R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. Addition of IL-18 binding protein (IL-18BP), the constitutive inhibitor of IL-18 activity, to the perifusate during and after I͞R resulted in improved contractile function after I͞R from 35% of control to 76% with IL-18BP. IL-18BP treatment also preserved intracellular tissue creatine kinase levels (by 420%). Steady-state mRNA levels for IL-18 were elevated after I͞R, and the concentration of IL-18 in myocardial homogenates was increased (control, 5.8 pg͞mg vs. I͞R, 26 pg͞mg; P < 0.01). Active IL-18 requires cleavage of its precursor form by the IL-1-converting enzyme (caspase 1); inhibition of caspase 1 also attenuated the depression in contractile force after I͞R (from 35% of control to 75.8% in treated atrial muscle; P < 0.01). Because caspase 1 also cleaves the precursor IL-1, IL-1 receptor blockade was accomplished by using the IL-1 receptor antagonist. IL-1 receptor antagonist added to the perifusate also resulted in a reduction of ischemia-induced contractile dysfunction. These studies demonstrate that endogenous IL-18 and IL-1 play a significant role in I͞R-induced human myocardial injury and that inhibition of caspase 1 reduces the processing of endogenous precursors of IL-18 and IL-1 and thereby prevents ischemia-induced myocardial dysfunction.
Surgery remains an important adjunct to medical therapy for the treatment of multi-drug resistant Mycobacterium tuberculosis. In the setting of localized disease, persistent sputum positivity, or patient intolerance of medical therapy, pulmonary resection should be undertaken. Pulmonary resection for multi-drug resistant tuberculosis can be performed with acceptable operative morbidity and mortality.
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