Diverse Cavity Types and Evidence that Mechanical Action on the Necrotic Granuloma Drives Tuberculous Cavitation

Abstract

Effacement of normal lung parenchyma by cavities is an important sequela of pulmonary tuberculosis. Despite its clinical significance, the pathogenesis of tuberculous cavitation is poorly understood, with controversy as to whether the fundamental mechanism involves matrix depletion, lipid pneumonia, or mechanical factors. In this study, a repetitive aerosol infection model using Mycobacterium tuberculosis was used to generate cavities in 20 New Zealand white rabbits. Serial computed tomography was performed to monitor cavity progression over 14 weeks. Three-dimensional reconstructions were compiled for each time point, allowing comprehensive four-dimensional cavity mapping. Terminally, cavities were processed for histopathology. Cavities progressed rapidly from areas of consolidation, and often showed a pattern of explosive growth followed by gradual contraction. Cavities formed preferentially in the caudodorsal lung fields, and frequently were subpleural. Cavitation was associated invariably with necrosis. Histomorphology showed four distinct cavity types that provide mechanistic clues and insight on early cavity development. Our study shows that cavitation is a highly dynamic process with preferential formation at sites of high mechanical stress. These findings suggest a model for the pathogenesis of tuberculous cavitation in which mechanical stress acts on the necrotic granuloma to produce acute tears in structurally weakened tissue, with subsequent air trapping and cavity expansion.