Towards a 'human-like' model of tuberculosis: Intranasal inoculation of LPS induces intragranulomatous lung necrosis in mice infected aerogenically with Mycobacterium tuberculosis

It is well known that one of the differences between murine and human tuber culosis is the lack of intragranulomatous necrosis in the former. The aim o f this study was to create a feasible and reproducible model of an experime ntal model of murine tuberculosis in which this necrosis should be present. Considering the Shwartzman reaction as a possible explanation for intragra nulomatous necrosis in human tuberculosis, C57Bl/6 mice, infected aerogenic ally with a virulent strain of Mycobacterium tuberculosis, were intranasall y inoculated with lipopolysaccharide (LPS) on day 19 postinfection (p.i.). Twenty-four hours later, neutrophils infiltrated the lung parenchyma in a s ignificant level, and 10 days after necrosis could be detected in the centr es of primary granulomas, that showed scanty macrophages and large amounts of collagen on an eosinophilic background. On the other hand, a significant decrease in the concentration of colony forming units (CFU) could be appre ciated 24 h after the LPS inoculation. Afterwards, nonbronchogenic spreadin g of granulomas increased and higher levels of interferon (IFN)-gamma mRNA were detected. These results lend support to the Shwartzman reaction as the origin of the intragranulomatous necrosis in the M. tuberculosis infection , and provides a useful tool to improve experimental murine models in tuber culosis.