Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

Hughes, Michael; McGettrick, Helen M.; Sapey, Elizabeth

doi:10.1183/16000617.0102-2019

Cited by 39 publications

(19 citation statements)

References 165 publications

(186 reference statements)

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“…These findings were then confirm in T2DM patients where 3 months of oral sildenafil (100 mg/day) reduced the endothelial function marker P‐selectin 49 . In pre‐clinical, as well as in clinical studies using chronic PDE5i with sildenafil 100 mg daily, we and others have shown that the NO‐cGMP‐PDE5 pathway and related targets are involved in the pathogenesis of several complications of diabetes affecting the immune system, 46‐48 adipose tissue, 50,51 and renal function 39 . A dose of 50mg of Sildenafil, given twice a week, was shown to improve surrogate markers of endothelial function (C‐reactive protein, endothelin‐1 and ICAM‐1, ANG‐1/TIE2 axis), modulating the number of circulating proangiogenic cells and exerting an anti‐inflammatory response in T2Dm patients 52 …”

Section: Introductionsupporting

confidence: 64%

“…[46][47][48] These findings were then confirm in T2DM patients where 3 months of oral sildenafil (100 mg/day) reduced the endothelial function marker P-selectin. 49 In pre-clinical, as well as in clinical studies using chronic PDE5i with sildenafil 100 mg daily, we and others have shown that the NO-cGMP-PDE5 pathway and related targets are involved in the pathogenesis of several complications of diabetes affecting the immune system, [46][47][48] adipose tissue, 50,51 and renal function. Its expression in men 53 is even higher, making them more responsive to PDE5i, as revealed in pulmonary hypertension (PH) and fibrosis.…”

Section: Introductionmentioning

confidence: 54%

“…In mouse models of diabetes, sildenafil restores normal levels of circulating TIE2‐expressing monocytes (TEMs), limiting inflammation, and promoting tissue repair 46‐48 . These findings were then confirm in T2DM patients where 3 months of oral sildenafil (100 mg/day) reduced the endothelial function marker P‐selectin 49 .…”

Section: Introductionmentioning

confidence: 76%

“…Chronic (6 months) PDE5 inhibition through vardenafil 10 mg/die has been shown to preserve endothelial function in T2DM patients, 45 probably due to an increase in angiogenic mediators, including Ang1 46 . These effects seem particularly important given that neutrophils isolated from patients with T2DM release larger amounts of proinflammatory cytokines, above all TNF‐α and IL‐6, 47 main players of the cytokine storm seen in COVID‐19 infection.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the NO‐cGMP‐PDE5 pathway in COVID‐19 infection. The DEDALO project

et al. 2020

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Background A pandemic outbreak of COVID‐19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, “cytokines storm,” that causes the systemic complications of COVID‐19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability. Objectives Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)‐cyclic GMP‐phosphodiesterase type 5 (PDE5) pathway in modulating low‐grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti‐inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID‐19 disease. Materials and methods We performed a systematic review of all evidence documenting any involvement of the NO‐cGMP‐PDE5 axis in the pathophysiology of COVID‐19, presenting the ongoing clinical trials aimed at modulating this axis, including our own “silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID‐19 (DEDALO trial).” Results The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID‐19 by (i) counteracting the Ang‐II‐mediated downregulation of AT‐1 receptor; (ii) acting on monocyte switching, thus reducing pro‐inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage‐necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications. Discussion and Conclusion If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID‐19 in developing countries.

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Section: Introductionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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Targeting the NO‐cGMP‐PDE5 pathway in COVID‐19 infection. The DEDALO project

et al. 2020

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“…Neutrophils are the most abundant leukocytes, which play a crucial role in diabetes mellitus pathogenesis and its related vascular complications [ 3 , 4 ]. In patients with diabetes mellitus, clinical researchers have found defective neutrophil functions, increased leukocyte counts, and cell morphological changes [ 5 , 6 , 7 ]. Developing a comprehensive and robust neutrophil phenotyping strategy is crucial for clarifying the pathogenesis in diabetes and related metabolic diseases.…”

Section: Introductionmentioning

confidence: 99%

A Novel Microfluidic Device for the Neutrophil Functional Phenotype Analysis: Effects of Glucose and Its Derivatives AGEs

et al. 2021

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Neutrophil dysfunction is closely related to the pathophysiology of patients with diabetes mellitus, but existing immunoassays are difficult to implement in clinical applications, and neutrophil’s chemotaxis as a functional biomarker for diabetes mellitus prognostic remains largely unexplored. Herein, a novel microfluidic device consisted of four independent test units with four cell docking structures was developed to study the neutrophil chemotaxis, which allowed multiple cell migration observations under a single field of view (FOV) and guaranteed more reliable results. In vitro studies, the chemotaxis of healthy neutrophils to N-Formyl-Met-Leu-Phe (fMLP) gradient (0, 10, 100, and 1000 nM) was concentration-dependent. The distinct promotion or suppression in the chemotaxis of metformin or pravastatin pretreated cells were observed after exposure to 100 nM fMLP gradient, indicating the feasibility and efficiency of this novel microfluidic device for clinically relevant evaluation of neutrophil functional phenotype. Further, the chemotaxis of neutrophils pretreated with 25, 50, or 70 mM of glucose was quantitatively lower than that of the control groups (i.e., 5 mM normal serum level). Neutrophils exposed to highly concentrated advanced glycation end products (AGEs) (0.2, 0.5, or 1.0 μM; 0.13 μM normal serum AGEs level), a product of prolonged hyperglycemia, showed that the higher the AGEs concentration was, the weaker the migration speed became. Specifically, neutrophils exposed to high concentrations of glucose or AGEs also showed a stronger drifting along with the flow, further demonstrating the change of neutrophil chemotaxis. Interestingly, adding the N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1) (i.e., high-affinity RAGE inhibitor) into the migration medium with AGEs could hinder the binding between AGEs and AGE receptor (RAGE) located on the neutrophil, thereby keeping the normal chemotaxis of neutrophils than the ones incubated with AGEs alone. These results revealed the negative effects of high concentrations of glucose and AGEs on the neutrophil chemotaxis, suggesting that patients with diabetes should manage serum AGEs and also pay attention to blood glucose indexes. Overall, this novel microfluidic device could significantly characterize the chemotaxis of neutrophils and have the potential to be further improved into a tool for risk stratification of diabetes mellitus.

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Microfluidic Impedance‐Deformability Cytometry for Label‐Free Single Neutrophil Mechanophenotyping

Petchakup

Yang

Gong

et al. 2022

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genic threats, they contribute to various host-defense mechanisms namely phagocytosis, chemotaxis, and formation of neutrophil extracellular traps (NETs). As neutrophil dysfunctions are implicated in various diseases such as cancer, [2,3] diabetes, [4,5] and cardiovascular diseases, [6] quantitative profiling of neutrophil activation and their functions can potentially reveal host immune health and facilitates clinical diagnostics. Conventional immunoassays for neutrophils include measuring surface markers expression by imaging or flow cytometry, [7] and secreted cytokines/ enzymes using enzyme linked immunosorbent assay (ELISA). [8] However, these biochemical approaches are expensive due to antibodies reagents, require laborious sample preparations, and thus not suitable for clinical testing applications.To address these issues, novel approaches have been proposed to study neutrophil functions [9][10][11] and intrinsic biophysical properties (e.g., cell deformability [12][13][14] and cell impedance [15,16] ) which are widely reported as promising label-free biomarkers which are implicated in diseases [17][18][19] and correlated to cell activation. [15,20] Cell deformability is a powerful biophysical marker for identifying cell diseases and cellular states, [21] and has been reported for leukocyte activation studies [22] and sepsis diagnosis. [23] Conventional biomechanical tools for single cell studies include atomic force microscopy (AFM), micropipette aspiration, and optical tweezers. AFM utilizes a small cantilever for indentation of a single cell, while micropipette aspiration applies a suction force to deform the cells and measure localized mechanical properties. Optical stretching relies on focused laser beams to trap and stretch single cells. All these techniques can be used with different forces (pN-µN) or time scales (strain rates) to study contributions of different cellular components on mechanical properties. For example, probing at low strain rates can provide information about actin cytoskeleton, [24] while probing at high strain rates can study cell nucleus such as chromatin and nuclear membrane elasticity. [19] While these techniques are highly useful for mechanobiology research, they have low throughput (<1 cell min −1 ) which limit their use in clinical settings. To alleviate these limitations, various microfluidic deformability cytometers have been proposed to probe cell deformation induced by hydrodynamic flow [25][26][27] or channel constrictions [28,29] using high speed imaging, which require expensive and bulky microscopy systems with highThe intrinsic biophysical states of neutrophils are associated with immune dysfunctions in diseases. While advanced image-based biophysical flow cytometers can probe cell deformability at high throughput, it is nontrivial to couple different sensing modalities (e.g., electrical) to measure other critical cell attributes including cell viability and membrane integrity. Herein, an "optics-free" impedance-deformability cytometer for multiparametric single ce...

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Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

Cited by 39 publications

References 165 publications

Targeting the NO‐cGMP‐PDE5 pathway in COVID‐19 infection. The DEDALO project

Targeting the NO‐cGMP‐PDE5 pathway in COVID‐19 infection. The DEDALO project

A Novel Microfluidic Device for the Neutrophil Functional Phenotype Analysis: Effects of Glucose and Its Derivatives AGEs

Microfluidic Impedance‐Deformability Cytometry for Label‐Free Single Neutrophil Mechanophenotyping

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