Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis

Fox, Katharine; Kirwan, Daniela E.; Whittington, Alex; Krishnan, Nitya; Gilman, Robert H.; López, José W.; Singh, Shivani; Porter, Joanna C.; Friedland, Jon S.

doi:10.1164/rccm.201710-2102oc

Cited by 52 publications

(58 citation statements)

References 47 publications

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“…The role of PLT is not limited to acute hemostasis and vascular wall repair. Increasing evidence indicates that PLT are the key effector cells through which the host regulates inflammatory responses and that PLT contribute to the initiation and spreading of local and systemic inflammation [27, 28]. PLT may induce T lymphocyte adhesion by secreting the key chemical inducer RANTES (regulated on activation, normal T-cell expressed and secreted, also known as CCL5), thereby regulating the functions of T lymphocytes [27, 29, 30].…”

Section: Discussionmentioning

confidence: 99%

Quantitative investigation of factors relevant to the T cell spot test for tuberculosis infection in active tuberculosis

Yang

Jiang

et al. 2019

Preprint

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23Background 24 Previous qualitative studies suggested that the false negative rate of T cell spot test 25 for tuberculosis infection (T-SPOT.TB) is associated with many risk factors in 26 tuberculosis patients; However, more precise quantitative studies are not well known. 27 Objective 28 To investigate the factors affecting quantified T-SPOT.TB in patients with active 29 tuberculosis.30Methods 31 We retrospectively analyzed the data of 360 patients who met the inclusion criteria. 32 Using the levels of early secreted antigenic target 6 kDa (ESAT-6) and culture filtrate 33 protein 10 kDa (CFP-10) as dependent variables, variables with statistical 34 significance in the univariate analysis were subjected to optimal scaling regression 35 analysis. 36 Results 37The results showed that the ESAT-6 regression model had statistical significance 38 (P-trend < 0.001) and that previously treated cases, CD4+ and platelet count were its 39 independent risk factors (all P-trend < 0.05); their importance levels were 0.095, 40 0.596 and 0.100, respectively, with a total of 0.791. The CFP-10 regression model 41 also had statistical significance (P-trend < 0.001); platelet distribution width and 42 alpha-2 globulin were its independent risk factors (all P-trend < 0.05), their 43 importance levels were 0.287 and 0.247, respectively, with a total of 0.534. The 44 quantification graph showed that quantified T-SPOT.TB levels had a linear correlation 45 3 with risk factors. 46 Conclusion 47 The test results of T-SPOT.TB should be given more precise explanations, especially 48 in patients with low levels of CD4+, platelet, alpha-2 globulin and high platelet 49 distribution width. 50 51 Introduction 52 The interferon-gamma release assay (IGRA) represents one of the most important 53 advances in the immunodiagnosis of Mycobacterium tuberculosis (MTB) infection in 54 the past two decades. As a new adjuvant method for the diagnosis of MTB infection, 55 IGRA has been widely applied and accepted clinically. In principle, IGRA determines 56 whether the subject is infected with MTB by examination of the levels of released 57 γ -interferon (IFN-γ) after stimulation of whole blood or peripheral blood mononuclear 58 cells (PBMCs) with MTB-specific antigen. This test is not affected by Bacillus 59 Calmette-Guerin (BCG) vaccination [1], a feature that is very beneficial in countries 60 such as China in which general BCG vaccination is practiced. Currently, the T cell 61 spot test for tuberculosis infection (T-SPOT.TB) is the main IGRA test method; it 62 provides intuitive and reproducible results and quantitatively reflects the number of 63 IFN-γ secreting cells in preparations of PBMCs [2]. 64 IGRA still has a certain false negative rate among patients with tuberculosis (TB). 65 Previous studies reported that negative bacteria in sputum [3-5], hypoproteinemia 66 [6-8], combined HIV infection [4, 7, 9], anti-TB treatment [10, 11], medical history [8, 67 4 12], anemia [6, 13], diabetes [14], parasitic infections [13], noncavitary lesion...

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Section: Discussionmentioning

confidence: 99%

Quantitative investigation of factors relevant to the T cell spot test for tuberculosis infection in active tuberculosis

Yang

Jiang

et al. 2019

Preprint

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“…Since it has been reported that culture conversion occurs earlier than lung tissue repair [17], it would be very helpful to evaluate serum markers of tissue repair [170,171] as relapse-free indicators of treatment outcome, without assessing pulmonary pathology by chest radiography or PET/CT. Good candidates are markers of platelet activity, since they are increased in plasma of patients with pulmonary TB, when compared to healthy controls, and then normalise after antimycobacterial treatment [4]. Additional candidates are the evaluation of the proportions of M. tuberculosis-specific CD27low CD4 + T-cells, which decline in parallel to the reduction of lung tissue damage [65].…”

Section: Modulation Of Monocytic and Lymphocytic Cell Populationsmentioning

confidence: 99%

“…In drug-susceptible TB, treatment beyond 2 months is needed to clear remaining drug-tolerant Mycobacterium tuberculosis bacilli [3]. Shortening this continuation phase to <4 months has led to relapse in up to 40% of patients, depending on the drug combination [4]. Long treatment is a considerable burden on patients and health services and elevates risk of nonadherence and noncompletion [5].…”

Section: Introductionmentioning

confidence: 99%

“…Shortening TB treatment is a major research goal [6] and several approaches are being pursued, including increased doses of existing drugs, use of repurposed drugs, development of new drugs and adjunctive host-directed therapies [5]. Trials done in the 1970s showed that a course of streptomycin, rifampicin, isoniazid and pyrazinamide even as short as 2-3 months resulted in relapse rates of <22% during the first 18 months after treatment completion [4]. This implies that the majority of patients in which the standard 6-month protocol is effective could be cured with a much shorter treatment.…”

Section: Introductionmentioning

confidence: 99%

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Can we predict tuberculosis cure? What tools are available?

et al. 2018

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Antibiotic treatment of tuberculosis takes ≥6 months, putting a major burden on patients and health systems in large parts of the world. Treatment beyond 2 months is needed to prevent tuberculosis relapse by clearing remaining, drug-tolerantMycobacterium tuberculosisbacilli. However, the majority of patients treated for only 2–3 months will cure without relapse and do not need prolonged treatment. Assays that can identify these patients at an early stage of treatment may significantly help reduce the treatment burden, while a test to identify those patients who will fail treatment may help target host-directed therapies.In this review we summarise the state of the art with regard to discovery of biomarkers that predict relapse-free cure for pulmonary tuberculosis. Positron emission tomography/computed tomography scanning to measure pulmonary inflammation enhances our understanding of “cure”. Several microbiological and immunological markers seem promising; however, they still need a formal validation. In parallel, new research strategies are needed to generate reliable tests.

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“…Platelets are key mediators in immunity and tissue remodelling and represent an abundant source of TGFβ1 [10]. During pulmonary TB infection, platelets promote inflammation and extracellular matrix (ECM) degradation [11]. Platelets also attenuate liver fibrosis by degrading ECM [12], whilst platelet-derived TGFβ1 is pathogenic in cardiac fibrosis [13].…”

Section: Introductionmentioning

confidence: 99%

Platelet counts predict prognosis in IPF, but are not the main source of pulmonary TGFβ1

Chong

Mikolasch

Sahota

et al. 2020

Preprint

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Transforming growth factor-β1 (TGFβ1) is the key pro-fibrotic cytokine implicated in the interstitial lung diseases (ILD), including idiopathic pulmonary fibrosis (IPF), but the primary source of TGFβ1 in these diseases is unknown. Platelets have abundant TGFβ1 stores, however their role in IPF is ill-defined. We sought to investigate whether platelets or platelet-derived TGFβ1 mediate IPF disease progression.ILD/IPF and non-ILD patients were recruited to determine platelet reactivity and followed for mortality. To study whether platelet-derived TGFβ1 modulates pulmonary fibrosis, mice with a targeted deletion of TGFβ1 in megakaryocytes and platelets (TGFβ1 fl/fl .PF4-Cre) were used in the bleomycin-induced PF model.We found a significantly higher mortality in IPF patients with elevated platelet counts, along with significantly increased platelets, neutrophils, TGFβ1 and CCL5 in the lung and bronchoalveolar lavage (BAL) of ILD patients. Despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation or fibrosis were significantly different between TGFβ1 fl/fl .PF4-Cre and control mice.Our results demonstrate for the first-time that platelet-derived TGFβ1 is redundant in driving pulmonary fibrosis in an animal model. However, platelets can predict mortality in IPF implicating other platelet-derived mediators, such as CCL5, in promoting human IPF disease.

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Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis

Cited by 52 publications

References 47 publications

Quantitative investigation of factors relevant to the T cell spot test for tuberculosis infection in active tuberculosis

Quantitative investigation of factors relevant to the T cell spot test for tuberculosis infection in active tuberculosis

Can we predict tuberculosis cure? What tools are available?

Platelet counts predict prognosis in IPF, but are not the main source of pulmonary TGFβ1

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