Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-α. A TNF-α neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.
We report the case of a 55-year-old male patient who presented with non-specific pulmonary symptoms (cough, haemoptysis, fever up to 39 degrees C, night sweats and weight loss). After empirical antibiotic therapy prescribed by his primary care physician, the patient showed no improvement in symptoms. Laboratory findings were: elevated C-reactive protein and C-ANCA, leukocytosis and thrombocytosis, and anaemia. Chest radiography showed disseminated nodules bilaterally. On multidetector-row computed tomography (MDCT), the bronchial walls showed a significant thickening and extensive peribronchiolar consolidations. Bronchoscopy revealed diffuse erythema of the tracheobronchial mucosa with diffusely scattered white plaques. Histopathology described a multifocal ulcerative bronchitis with underlying chronic bronchitis. These findings in combination with the laboratory data lead to the diagnosis of Wegener's granulomatosis. Consequently, we started with an immunosuppressive therapy. Chest radiography after 10 days showed marked resolution of the infiltrates. Within 1 month, the patient became asymptomatic.
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