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.

An unusual case of eosinophilic lung disease with multiple cyst formation

“…Third, the alveolar spaces in the lesions expanded to reduce the tissue defects after a subsequent spontaneous resolution. In our case, the formation of thin-walled cysts might have been associated variably with a mechanism similar to that proposed by Ihms et al [ 14 ]. Additionally, the severe tissue-damaging inflammation might have led to the continuous accumulation of leaked air in the tissue defects, leading to pulmonary pneumatoceles [ 17 , 18 ].…”

“…The patient presented with an eosinophilic lung disease that manifested clinically as the formation of multiple cysts, which resolved spontaneously. In a high-resolution CT and histopathological analysis of a rabbit model of tuberculous cavities, Ihms et al reported that all cavities were pathologically associated with the central necrotic areas of granulomas and that a certain level of communication was observed between the cavities and respiratory tract [ 14 ]. Based on the results, they proposed the following mechanisms of thin-walled cavity formation and progression: 1) with inspiration, external tension in the surrounding lung tissue pulls air into the necrotic center, 2) if the outlet is severely obstructed creating a ball-valve effect, extreme air trapping occurs and causes the cavity to assume a thin-walled morphology.…”

The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas

“…Mice were infected by Mtb H37Rv using a Glas-Col chamber, and mice were sacrificed for enumeration of Mtb CFU in lungs and spleen day 1 counts as well as subsequent time points as previously described (67). H&E stained tissue sections were imaged by high resolution digital microscopy and lesion scoring was performed as described (68). High resolution PET/CT imaging was conducted using a Mediso nanoScan instrument.…”

The integrated stress response mediates type I interferon driven necrosis in Mycobacterium tuberculosis granulomas

“…Mice were infected by Mtb H37Rv using a Glas-Col chamber, and mice were sacrificed for enumeration of Mtb CFU in lungs and spleen day 1 counts as well as subsequent time points as previously described 86 . H&E stained tissue sections were imaged by high resolution digital microscopy and lesion scoring was performed as described 87 . High resolution PET/CT imaging was conducted using a Mediso nanoScan instrument.…”