Dataset Information

Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis.

ABSTRACT: Cavitation in tuberculosis enables highly efficient person-to-person aerosol transmission. We performed transcriptomics in the rabbit cavitary tuberculosis model. Among 17 318 transcripts, we identified 22 upregulated proteases. Five type I collagenases were overrepresented: cathepsin K (CTSK), mast cell chymase-1 (CMA1), matrix metalloproteinase 1 (MMP-1), MMP-13, and MMP-14. Studies of collagen turnover markers, specifically, collagen type I C-terminal propeptide (CICP), urinary deoxypyridinoline (DPD), and urinary helical peptide, revealed that cavitation in tuberculosis leads to both type I collagen destruction and synthesis and that proteases other than MMP-1, MMP-13, and MMP-14 are involved, suggesting a key role for CTSK. We confirmed the importance of CTSK upregulation in human lung specimens, using immunohistochemical analysis, which revealed perigranulomatous staining for CTSK, and we showed that CTSK levels were increased in the serum of patients with tuberculosis, compared with those in controls (3.3 vs 0.3 ng/mL; P = .005).

SUBMITTER: Kubler A

PROVIDER: S-EPMC4721912 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis.

Kubler Andre A Larsson Christer C Luna Brian B Andrade Bruno B BB Amaral Eduardo P EP Urbanowski Michael M Orandle Marlene M Bock Kevin K Ammerman Nicole C NC Cheung Laurene S LS Winglee Kathryn K Halushka Marc M Park Jin Kyun JK Sher Alan A Friedland Jon S JS Elkington Paul T PT Bishai William R WR

The Journal of infectious diseases 20150927 4

Cavitation in tuberculosis enables highly efficient person-to-person aerosol transmission. We performed transcriptomics in the rabbit cavitary tuberculosis model. Among 17 318 transcripts, we identified 22 upregulated proteases. Five type I collagenases were overrepresented: cathepsin K (CTSK), mast cell chymase-1 (CMA1), matrix metalloproteinase 1 (MMP-1), MMP-13, and MMP-14. Studies of collagen turnover markers, specifically, collagen type I C-terminal propeptide (CICP), urinary deoxypyridinol ...[more]

PMID: 26416658

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Project description:BACKGROUND:Delay in diagnosis and treatment of pulmonary tuberculosis (PTB) leads to severe disease, adverse outcomes and increased transmission. Assessing the extent of delay and its effect on disease progression in TB affected settings has clinical and programmatic importance. Hence, the aim of this study was to investigate the possible effect of delay on infectiousness (cavitation and smear positivity) of patients at diagnosis in Somali pastoralist area, Ethiopia. METHODS:A cross-sectional study was conducted between December 2017 and October 2018, and 434 newly coming and confirmed PTB patients aged ?15?years were recruited in five facilities. Data were collected using interview, record-review, anthropometry, Acid-fast bacilli and chest radiography techniques. Log-binomial regression models were used to reveal the association of delay and other factors associated with cavitation and smear positivity, and ROC Curve was used to determine discriminative ability and threshold delays. RESULTS:Median age of patients was 30?years. Of all, 62.9% were males, and 46.5% were pastoralists. Median diagnosis delay was 49?days (IQR?=?33-70). Cavitation was significantly associated with diagnosis delay [P?<?0.001]; 22.2% among patients diagnosed within 30?days of illness and 51.7% if delay was over 30?days. The threshold delay that optimizes cavitation was 43?days [AUC (95% CI)?=?0.67(0.62-0.72)]. Smear positivity was significantly increased in patients delayed over 49?days [p?=?0.02]. Other factors associated with cavitation were age???35?years [APR (95% CI) =1.3(1.01-1.6)], chronic diseases [APR (95% CI)?=?1.8(1.2-2.6)] and low MUAC*female [APR (95% CI)?=?1.8(1.2-2.8)]. Smear positivity was also associated with age???35?years [APR (95% CI) =1.4(1.1-1.8)], low BMI [APR (95% CI) =1.3(1.01-1.7)] and low MUAC [APR (95% CI) =1.5(1.2-1.9)]. CONCLUSION:This study highlights delay in diagnosis of pulmonary TB remained high and increased infectiousness of patients in pastoral settings of Ethiopia. Hence, delay should be targeted to improve patient outcomes and reduce transmission in such settings.

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of fibrillar collagens in the alveolar space resulting in reduced pulmonary function and a high mortality rate. Biomarkers measuring the turnover of type I and III collagen could provide valuable information for prognosis and treatment decisions in IPF.MethodsSerological biomarkers reflecting the formation of type III collagen (PRO-C3) and degradation of type I (C1M) and III collagen (C3M) were evaluated in a real-world cohort of 178 newly diagnosed IPF patients. Blood samples and clinical data were collected at baseline, six, and 12 months. Baseline and longitudinal biomarker levels were related to disease progression of IPF (defined as ≥ 5% decline in forced vital capacity (FVC) and/or ≥ 10% decline in diffusing capacity for carbon monoxide (DLco) and/or all-cause mortality at 12 months). Furthermore, we analysed differences in percentage change of biomarker levels from baseline between patients receiving antifibrotic treatment or not.ResultsIncreased baseline levels of type I and III collagen turnover biomarkers were associated with a greater risk of disease progression within 12 months compared to patients with a low baseline type I and III collagen turnover. Patients with progressive disease had higher serum levels of C1M (P = 0.038) and PRO-C3 (P = 0.0022) compared to those with stable disease over one year. There were no differences in biomarker levels between patients receiving pirfenidone, nintedanib, or no antifibrotics.ConclusionBaseline levels of type I and III collagen turnover were associated with disease progression within 12 months in a real-world cohort of IPF patients. Longitudinal biomarker levels of type I and III collagen turnover were related to progressive disease. Moreover, antifibrotic therapy did not affect type I and III collagen turnover biomarkers in these patients. PRO-C3 and C1M may be potential biomarkers for a progressive disease behavior in IPF.

Project description:The cholinergic system is present in both bacteria and mammals and regulates inflammation during bacterial respiratory infections through neuronal and non-neuronal production of acetylcholine (ACh) and its receptors. However, the presence of this system during the immunopathogenesis of pulmonary tuberculosis (TB) in vivo and in its causative agent Mycobacterium tuberculosis (Mtb) has not been studied. Therefore, we used an experimental model of progressive pulmonary TB in BALB/c mice to quantify pulmonary ACh using high-performance liquid chromatography during the course of the disease. In addition, we performed immunohistochemistry in lung tissue to determine the cellular expression of cholinergic system components, and then administered nicotinic receptor (nAChR) antagonists to validate their effect on lung bacterial burden, inflammation, and pro-inflammatory cytokines. Finally, we subjected Mtb cultures to colorimetric analysis to reveal the production of ACh and the effect of ACh and nAChR antagonists on Mtb growth. Our results show high concentrations of ACh and expression of its synthesizing enzyme choline acetyltransferase (ChAT) during early infection in lung epithelial cells and macrophages. During late progressive TB, lung ACh upregulation was even higher and coincided with ChAT and ?7 nAChR subunit expression in immune cells. Moreover, the administration of nAChR antagonists increased pro-inflammatory cytokines, reduced bacillary loads and synergized with antibiotic therapy in multidrug resistant TB. Finally, in vitro studies revealed that the bacteria is capable of producing nanomolar concentrations of ACh in liquid culture. In addition, the administration of ACh and nicotinic antagonists to Mtb cultures induced or inhibited bacterial proliferation, respectively. These results suggest that Mtb possesses a cholinergic system and upregulates the lung non-neuronal cholinergic system, particularly during late progressive TB. The upregulation of the cholinergic system during infection could aid both bacterial growth and immunomodulation within the lung to favor disease progression. Furthermore, the therapeutic efficacy of modulating this system suggests that it could be a target for treating the disease.

Dataset Information

Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis.

Publications

Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis.

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