Zur Histochemie der Lungentuberkulose, mit besonderer Berücksichtigung der Fettsubstanzen und Lipoide

Pagel, Walter; Pagel, Mark

doi:10.1007/bf01891650

Cited by 28 publications

(16 citation statements)

References 8 publications

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“…The characteristic lesion, a caseating granuloma, is a localized lesion in tissue consisting of a central area of caseous necrosis surrounded by epitheloid macrophages and then lymphocytes, Figure 1. Caseation necrosis was termed ‘fatty metamorphosis’ by Virchow because it contains abundant lipid and foamy macrophages 9, 23, 33 . Caseation is a process of coagulation necrosis in which lipid rich cells disintegrate and are converted into a homogeneous, structure less mass devoid of blood vessels 19, 23, 34 .…”

Section: Resultsmentioning

confidence: 99%

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Pathology of post primary tuberculosis of the lung: An illustrated critical review

2011

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Post primary tuberculosis occurs in immunocompetent adults, is restricted to the lungs and accounts for 80% of all clinical cases and nearly 100% of transmission of infection. The supply of human tissues with post primary tuberculosis plummeted with the introduction of antibiotics decades before the flowering of research using molecular methods in animal models. Unfortunately, the paucity of human tissues prevented validation of the models. As a result, it is a paradigm of contemporary research that caseating granulomas are the characteristic lesion of all tuberculosis and that cavities form when they erode into bronchi. This differs from descriptions of the preantibiotic era when many investigators had access to thousands of cases. They reported that post primary tuberculosis begins as an exudative reaction: a tuberculous lipid pneumonia of foamy alveolar macrophages that undergoes caseation necrosis and fragmentation to produce cavities. Granulomas in post primary disease arise only in response to old caseous pneumonia and produce fibrosis, not cavities. We confirmed and extended these observations with study of 104 cases of untreated tuberculosis. In addition, studies of the lungs of infants and immunosuppressed adults revealed a second type of tuberculous pneumonia that seldom produces cavities. Since the concept that cavities arise from caseating granulomas was supported by studies of animals infected with Mycobacterium bovis, we investigated its pathology. We found that M. bovis does not produce post primary tuberculosis in any species. It only produces an aggressive primary tuberculosis that can develop small cavities by erosion of caseating granulomas. Consequently, a key unresolved question in the pathogenesis of tuberculosis is identification of the mechanisms by which Mycobacterium tuberculosis establish a localized safe haven in alveolar macrophages in an otherwise solidly immune host where it can develop conditions for formation of cavities and transmission to new hosts.

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Section: Resultsmentioning

confidence: 99%

“…Foci of adjacent alveoli become filled with foamy alveolar macrophages and lipoid debris to from the “buds”. Alveolar macrophages become increasingly foamy and then degenerate leaving lipoid debris and rare acid-fast bacilli in alveoli 33 . This produces the ground glass appearance on radiographs 44, 46 .…”

Section: Resultsmentioning

confidence: 99%

Pathology of post primary tuberculosis of the lung: An illustrated critical review

2011

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“…Canetti, Pagel and Medlar all agreed that the pneumonic infection is a lipid pneumonia that spreads in the lung via bronchi, not via lymphatics or the blood stream and that it is frequently paucibacillary meaning that it contains few or no detectable acid fast bacilli 21–23 . Pagel used fat stains on sections of multiple stages of pulmonary tuberculosis to demonstrate that stainable lipid increases progressively within foamy alveolar macrophages with development of the pneumonic lesions 27 . Finally, clinical disease frequently had an acute onset resembling community acquired pneumonia and cavities formed by dissolution of caseous pneumonia.…”

Section: Introductionmentioning

confidence: 99%

Tuberculosis as a three-act play: A new paradigm for the pathogenesis of pulmonary tuberculosis

2016

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Lack of access to human tissues with untreated tuberculosis (TB) has forced generations of researchers to use animal models and to adopt a paradigm that granulomas are the characteristic lesion of both primary and post primary TB. An extended search of studies of human lung tissues failed to find any reports that support this paradigm. We found scores of publications from gross pathology in 1804 through high resolution CT scans in 2015 that identify obstructive lobular pneumonia, not granulomas, as the characteristic lesion of developing post-primary TB. This paper reviews this literature together with other relevant observations to formulate a new paradigm of TB with three distinct stages: a three-act play. First, primary TB, a war of attrition, begins with infection that spreads via lymphatics and blood stream before inducing systemic immunity that contains and controls the organisms within granulomas. Second, post-primary TB, a sneak attack, develops during latent TB as an asymptomatic obstructive lobular pneumonia in persons with effective systemic immunity. It is a paucibacillary process with no granulomas that spreads via bronchi and accumulates mycobacterial antigens and host lipids for 1–2 years before suddenly undergoing caseous necrosis. Third, the fallout, is responsible for nearly all clinical post primary disease. It begins with caseous necrotic pneumonia that is either retained to become the focus of fibrocaseous disease or is coughed out to leave a cavity. This three-stage paradigm suggests testable hypotheses and plausible answers to long standing questions of immunity to TB.

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“…Although it was well known that saprophytic mycobacteria could metabolize cholesterol (3), it was only recently demonstrated that pathogenic strains can also utilize this nutrient as a growth substrate (4,5). Interestingly, cholesterol has been found in high concentrations within caseating granulomas in both humans and mice (6,7), and bacteria have been observed congregating around cholesterol foci (7). Highlighting the importance of cholesterol in bacterial pathogenesis, the deletion of genes involved in cholesterol metabolism reduces the virulence of M. tuberculosis (5,8).…”

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Characterization of a Carbon-Carbon Hydrolase from Mycobacterium tuberculosis Involved in Cholesterol Metabolism

Lack

Yam

Lowe

et al. 2010

Journal of Biological Chemistry

125

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In the recently identified cholesterol catabolic pathway of Mycobacterium tuberculosis, 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate hydrolase (HsaD) is proposed to catalyze the hydrolysis of a carbon-carbon bond in 4,5-9,10-diseco-3-hydroxy-5,9,17-tri-oxoandrosta-1(10),2-diene-4-oic acid (DSHA), the cholesterol meta-cleavage product (MCP) and has been implicated in the intracellular survival of the pathogen. Herein, purified HsaD demonstrated 4 -33 times higher specificity for DSHA (k cat /K m ‫؍‬ 3.3 ؎ 0.3 ؋ 10 4 M ؊1 s ؊1 ) than for the biphenyl MCP 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) and the synthetic analogue 8-(2-chlorophenyl)-2-hydroxy-5-methyl-6-oxoocta-2,4-dienoic acid (HOPODA), respectively. The S114A variant of HsaD, in which the active site serine was substituted with alanine, was catalytically impaired and bound DSHA with a K d of 51 ؎ 2 M. The S114A⅐DSHA species absorbed maximally at 456 nm, 60 nm red-shifted versus the DSHA enolate. Crystal structures of the variant in complex with HOPDA, HOPODA, or DSHA to 1.8 -1.9 Å indicate that this shift is due to the enzyme-induced strain of the enolate. These data indicate that the catalytic serine catalyzes tautomerization. A second role for this residue is suggested by a solvent molecule whose position in all structures is consistent with its activation by the serine for the nucleophilic attack of the substrate. Finally, the ␣-helical lid covering the active site displayed a ligand-dependent conformational change involving differences in side chain carbon positions of up to 6.7 Å , supporting a two-conformation enzymatic mechanism. Overall, these results provide novel insights into the determinants of specificity in a mycobacterial cholesterol-degrading enzyme as well as into the mechanism of MCP hydrolases.Mycobacterium tuberculosis is the leading cause of bacterial mortality, causing an estimated 2 million deaths/year (1). The mechanisms underlying the remarkable ability of this pathogen to survive for long periods of time within the host are poorly understood (2). Although it was well known that saprophytic mycobacteria could metabolize cholesterol (3), it was only recently demonstrated that pathogenic strains can also utilize this nutrient as a growth substrate (4, 5). Interestingly, cholesterol has been found in high concentrations within caseating granulomas in both humans and mice (6, 7), and bacteria have been observed congregating around cholesterol foci (7). Highlighting the importance of cholesterol in bacterial pathogenesis, the deletion of genes involved in cholesterol metabolism reduces the virulence of M. tuberculosis (5,8). Therefore, further knowledge of cholesterol metabolism in M. tuberculosis is crucial to our understanding of bacterial virulence.M. tuberculosis catabolizes cholesterol using a metabolic pathway similar to that identified in Rhodococcus jostii RHA1 (4, 9). In this pathway, the aerobic degradation of the fourringed steroid nucleus occurs through the opening of ring B, aromatization of ring A, and hydroxyla...

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Zur Histochemie der Lungentuberkulose, mit besonderer Berücksichtigung der Fettsubstanzen und Lipoide

Cited by 28 publications

References 8 publications

Pathology of post primary tuberculosis of the lung: An illustrated critical review

Pathology of post primary tuberculosis of the lung: An illustrated critical review

Tuberculosis as a three-act play: A new paradigm for the pathogenesis of pulmonary tuberculosis

Characterization of a Carbon-Carbon Hydrolase from Mycobacterium tuberculosis Involved in Cholesterol Metabolism

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