scholarly journals A blunted GPR183/oxysterol axis during dysglycemia results in delayed recruitment of macrophages to the lung during M. tuberculosis infection

2022 ◽  
Author(s):  
Minh Dao Ngo ◽  
Stacey Bartlett ◽  
Helle Bielefeldt-Ohmann ◽  
Cheng Xiang Foo ◽  
Roma Sinha ◽  
...  
Keyword(s):  
Mechanistic Explanation ◽  
Early Infection ◽  
Tuberculosis Infection ◽  
Lung Pathology ◽  
Patients With Diabetes ◽  
Chest X Ray ◽  
Cytochrome P450 Family ◽  
Deficient Mice ◽  
Severe Lung

We previously reported that the oxidised cholesterol-sensing receptor GPR183 is significantly downregulated in blood from tuberculosis (TB) patients with diabetes compared to TB patients without co-morbidities and that lower GPR183 expression in blood is associated with more severe pulmonary TB on chest-x-ray consistent with observations in dysglycemic mice. To further elucidate the role of this receptor and its endogenous high affinity agonist 7α,25-dihydroxycholesterol (7α,25-OHC) in the lung, we studied high fat diet (HFD)-induced 28 dysglycemic mice infected with M.tuberculosis. We found that the 7α,25-OHC-producing enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) were highly upregulated upon M.tuberculosis infection in the lungs of normoglycemic mice, and this was associated with increased expression of GPR183 indicative of effective recruitment of GPR183-expressing immune cells to the site of infection. We demonstrated that CYP7B1 was predominantly expressed by macrophages in the centre of TB granulomas. Expression of CYP7B1 was significantly blunted in lungs from HFD-fed dysglycemic animals and this coincided with 36 delayed recruitment of macrophages to the lung during early infection and more severe lung pathology. GPR183 deficient mice similarly had reduced macrophage recruitment during early infection demonstrating a requirement of the GPR183/oxysterol axis for macrophage infiltration into the lung in TB. Together our data demonstrate that oxidised cholesterols and GPR183 play an important role in positioning macrophages to the site of M. tuberculosis infection and that this is impaired by HFD-induced dysglycemia, adding a mechanistic explanation to the poorer TB outcomes in patients with diabetes.

scholarly journals Pediatric pleural empyema: one of the management challenges in children of Democratic Republic of Congo

2017 ◽  
Vol 39 (2) ◽  
Author(s):  
Kibwe Alphonse Simbi ◽  
Valentin Kazadi ◽  
Louis-Marie Aissi ◽  
François Mbahewaka Katsuva ◽  
Numbi Oscar Luboya ◽  
...  
Keyword(s):  
Low Income ◽  
Democratic Republic Of Congo ◽  
Pleural Empyema ◽  
Low Income Countries ◽  
British Thoracic Society ◽  
Rapid Improvement ◽  
Chest X Ray ◽  
Basic Medical ◽  
Severe Lung

Empyema is a serious complication characterized by purulent exudate and bacteria in the pleural space, which may progress to necrosis, cavitations or fistulas in the thoracic cavity. It remains a major challenge throughout low-income countries. Objectives were to emphasize the role of basic medical and radiologic approach and to resolve a severe lung complication when facilities are inadequate. A five-year-old female was referred with distress respiratory to the Emergency Unit of Monkole, a large public-private missionary hospital in Kinshasa, Congo. Chest X-ray showed a massive empyema that was resolved by immediate drainage and antibiotiocs. Results were rapid improvement and discharge after 3 weeks. A classic medical and imaging approach is a winning return in low-income countries. According to the British Thoracic Society guidelines, pleural effusion with compromising respiratory function can be managed by drainage and antibiotics.

scholarly journals UBXN3B Restricts Viral Pathogenesis by Maintaining Hematopoietic Homeostasis

2021 ◽  
Author(s):  
Tingting Geng ◽  
Duomeng Yang ◽  
Tao Lin ◽  
Andrew Harrison ◽  
Binsheng Wang ◽  
...  
Keyword(s):  
Viral Infection ◽  
Type I ◽  
Lung Pathology ◽  
Viral Loads ◽  
Type I Ifns ◽  
Multipotent Progenitors ◽  
Specific Immunoglobulin ◽  
The Right ◽  
Severe Lung

ABSTRACTHematopoiesis is finely regulated to enable timely production of the right number and type of mature immune cells to maintain tissue homeostasis. Dysregulated hematopoiesis may compromise antiviral immunity and/or exacerbate immunopathogenesis. Herein, we report an essential and new role of ubiquitin X domain containing gene 3B (UBXN3B) in balancing myelopoiesis and lymphopoiesis. Ubxn3b deficiency (Ubxn3b-/-) results in a remarkable increase in myeloid cells and neutrophil-to-lymphocyte ratio, along with a reduction in lymphocytes in steady-state mice. This dysregulation is exacerbated during viral infection and renders mice highly vulnerable to severe lung pathology induced by severe acute respiratory syndrome coronavirus 2 and arthritis by arthritogenic alphaviruses. Ubxn3b-/- mice present normal type I IFNs, higher viral loads and inflammatory mediators, lower virus-specific immunoglobulin G and slower resolution of disease, when compared to Ubxn3b+/+ littermates. Mechanistically, Ubxn3b-/- mice have fewer multipotent progenitors and common lymphoid progenitors, but more common myeloid progenitors. In particular, the precursor and immature B cell numbers are dramatically decreased in the bone marrow of Ubxn3b-/- mice. These data demonstrate that UBXN3B signaling is essential for restricting viral infection and immunopathogenesis by maintaining hematopoietic homeostasis.

scholarly journals Major Neutrophil-Derived Soluble Mediators Associate With Baseline Lung Pathology and Post-Treatment Recovery in Tuberculosis Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Caleb Nwongbouwoh Muefong ◽  
Olumuyiwa Owolabi ◽  
Simon Donkor ◽  
Salome Charalambous ◽  
Joseph Mendy ◽  
...  
Keyword(s):  
Bacterial Load ◽  
Lung Damage ◽  
Lung Pathology ◽  
Therapeutic Approaches ◽  
Gm Csf ◽  
Whole Cell Lysate ◽  
Tb Treatment ◽  
Chest X Ray ◽  
Multiplex Cytokine ◽  
Severe Lung

BackgroundThe inflammatory response to Mycobacterium tuberculosis results in variable degrees of lung pathology during active TB (ATB) with central involvement of neutrophils. Little is known about neutrophil-derived mediators and their role in disease severity at baseline and recovery upon TB treatment initiation.Methods107 adults with confirmed pulmonary TB were categorised based on lung pathology at baseline and following successful therapy using chest X-ray scores (Ralph scores) and GeneXpert bacterial load (Ct values). Plasma, sputum, and antigen-stimulated levels of MMP1, MMP3, MMP8, MMP9, MPO, S100A8/9, IL8, IL10, IL12/23(p40), GM-CSF, IFNγ, and TNF were analysed using multiplex cytokine arrays.ResultsAt baseline, neutrophil counts correlated with plasma levels of MMP8 (rho = 0.45, p = 2.80E−06), S100A8 (rho = 0.52, p = 3.00E−08) and GM-CSF (rho = 0.43, p = 7.90E−06). Levels of MMP8 (p = 3.00E−03), MMP1 (p = 1.40E−02), S100A8 (p = 1.80E−02) and IL12/23(p40) (p = 1.00E−02) were associated with severe lung damage, while sputum MPO levels were directly linked to lung damage (p = 1.80E−03), Mtb load (p = 2.10E−02) and lung recovery (p = 2.40E−02). Six months of TB therapy significantly decreased levels of major neutrophil-derived pro-inflammatory mediators: MMP1 (p = 4.90E−12 and p = 2.20E−07), MMP8 (p = 3.40E−14 and p = 1.30E−05) and MMP9 (p = 1.60E−04 and p = 1.50E−03) in plasma and sputum, respectively. Interestingly, following H37Rv whole cell lysate stimulation, S100A8 (p = 2.80E−02), MMP9 (p = 3.60E−02) and MPO (p = 9.10E−03) levels at month 6 were significantly higher compared to baseline. Sputum MMP1 (p = 1.50E−03), MMP3 (p = 7.58E−04), MMP9 (p = 2.60E−02) and TNF (p = 3.80E−02) levels were lower at month 6 compared to baseline in patients with good lung recovery.ConclusionIn this study, patients with severe lung pathology at baseline and persistent lung damage after treatment were associated with higher plasma and sputum levels of major pro-inflammatory neutrophil-derived mediators. Interestingly, low sputum MPO levels were associated with severe lung damage, higher Mtb burden and low recovery. Our data suggest that therapeutic agents which target these mediators should be considered for future studies on biomarkers and host-directed therapeutic approaches against TB-related lung pathology and/or lung recovery.

The role of angiopoetic factors in wound healing among patients with diabetes treated with negative-pressure wound therapy

Leczenie Ran ◽  
2015 ◽  
Vol 11 (4) ◽  
pp. 171-178
Author(s):  
Beata Mrozikiewicz-Rakowska ◽  
Joanna Kania ◽  
Ewelina Bucior ◽  
Adriana Nowak ◽  
Tomasz Grzela ◽  
...  
Keyword(s):  
Wound Healing ◽  
Negative Pressure ◽  
Negative Pressure Wound Therapy ◽  
Wound Therapy ◽  
Patients With Diabetes

Role of Methylglyoxal in Diabetic Cardiovascular and Kidney Diseases: Insights from Basic Science for Application into Clinical Practice

2018 ◽  
Vol 24 (26) ◽  
pp. 3072-3083 ◽  
Author(s):  
Sowndramalingam Sankaralingam ◽  
Angham Ibrahim ◽  
MD Mizanur Rahman ◽  
Ali H. Eid ◽  
Shankar Munusamy
Keyword(s):  
Therapeutic Strategy ◽  
Kidney Diseases ◽  
Vascular Dysfunction ◽  
Dicarbonyl Compound ◽  
Renal Complications ◽  
Lysine Residues ◽  
Patients With Diabetes ◽  
Prevalence Of Diabetes Mellitus

Background: The incidence and prevalence of diabetes mellitus are increasing globally at alarming rates. Cardiovascular and renal complications are the major cause of morbidity and mortality in patients with diabetes. Methylglyoxal (MG) - a highly reactive dicarbonyl compound – is increased in patients with diabetes and has been implicated to play a detrimental role in the etiology of cardiovascular and renal complications. Derived from glucose, MG binds to arginine and lysine residues in proteins, and the resultant end products serve as surrogate markers of MG generation in vivo. Under normal conditions, MG is detoxified by the enzyme glyoxalase 1 (Glo1), using reduced glutathione as a co-factor. Elevated levels of MG is known to cause endothelial and vascular dysfunction, oxidative stress and atherosclerosis; all of which are risk factors for cardiovascular diseases. Moreover, MG has also been shown to cause pathologic structural alterations and impair kidney function. Conversely, MG scavengers (such as N-acetylcysteine, aminoguanidine or metformin) or Nrf2/Glo1 activators (such as trans-resveratrol / hesperetin) are shown to be useful in preventing MG-induced cardiovascular and renal complications in diabetes. However, clinical evidence supporting the MG lowering properties of these agents are limited and hence, need further investigation. Conclusion: Reducing MG levels directly using scavengers or indirectly via activation of Nrf2/Glo1 may serve as a novel and potent therapeutic strategy to counter the deleterious effects of MG in diabetic complications.

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