Aflibercept regulates retinal inflammation elicited by high glucose via the PlGF/ERK pathway

Lazzara, Francesca; Fidilio, Annamaria; Platania, Chiara Bianca Maria; Giurdanella, Giovanni; Salomone, Salvatore; Leggio, Gian Marco; Tarallo, Valeria; Cicatiello, Valeria; Falco, Sandro De; Eandi, Chiara M; Drago, Filippo; Bucolo, Claudio

doi:10.1016/j.bcp.2019.07.021

Cited by 61 publications

(48 citation statements)

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“… Arden and Sivaprasad, 2012 ; Kurihara et al., 2014 ; Li et al., 2017 ). Furthermore, HIF-1α can induce expression of another proangiogenic factor, the PlGF ( Tudisco et al., 2014 ; Lazzara et al., 2019 ). In this study we found a correlation, in terms of time-dependent expression, between HIF-1α and PlGF, after CoCl 2 treatment ( Figure 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…Besides VEGFA, HIF-1α can also induce the placental growth factor (PlGF) ( Zimna and Kurpisz, 2015 ; Charnock-Jones, 2016 ; Mitsui et al., 2018 ), an emerging target in retinal neovascular diseases ( Kwon and Jee, 2018 ; Lee et al., 2018 ; Saddala et al., 2018 ; Lazzara et al., 2019 ; Van Bergen et al., 2019 ). Furthermore, HIF-1α is involved in expression of several microRNAs (miRNAs), that are named HypoxamiRs if they bear in their promoter region the hypoxia responsive elements (HREs) ( Nallamshetty et al., 2013 ; Bertero et al., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Stabilization of HIF-1α in Human Retinal Endothelial Cells Modulates Expression of miRNAs and Proangiogenic Growth Factors

et al. 2020

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Retinal hypoxia is one of the causative factors of diabetic retinopathy and is also one of the triggers of VEGF release. We hypothesized that specific dysregulated miRNAs in diabetic retinopathy could be linked to hypoxia-induced damage in human retinal endothelial cells (HRECs). We investigated in HRECs the effects of chemical (CoCl 2 ) hypoxia on the expression of HIF-1α, VEGF, PlGF, and of a focused set of miRNAs. We found that miR-20a-5p, miR-20b-5p, miR-27a-3p, miR-27b-3p, miR-206-3p, miR-381-3p correlated also with expression of TGFβ signaling pathway genes in HRECs, challenged with chemical hypoxic stimuli. In conclusion, our data suggest that retinal angiogenesis would be promoted, at least under HIF-1α activation, by upregulation of PlGF and other factors such as miRNAs, VEGFA, and TGFβ1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stabilization of HIF-1α in Human Retinal Endothelial Cells Modulates Expression of miRNAs and Proangiogenic Growth Factors

et al. 2020

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“…Overexpression of COX2 and p-p65/p65 greatly enhanced pulmonary fibrosis via enhancing the expression of pro-fibrotic cytokine TGF-β1 (34) and apoptosis markers, including Bax/Bcl-2 (35). TGF-β1 is critical for regulatory T cell function and T-helper (Th) 9 and Th17 differentiation, which play important roles in the regulation of tissue repair, embryogenesis, cartilage homeostasis, cellular growth and proliferation and cancer, and are associated with the development of autoimmune disorders, chronic inflammatory conditions and allergic diseases (36).…”

Section: Discussionmentioning

confidence: 99%

“…The MAPK pathway involves p38, JNK and ERK1/2, which play key roles in acute lung injury, and the ERK pathway exerts a critical function in the management of levels of various cytokines, including TNF-α, IL-1β and IL-6 ( 39 ). Furthermore, ERK is involved in the regulation of numerous cellular processes, including stress response, inflammatory pathways, proliferation, differentiation, apoptosis and survival ( 34 ). Elevated p-ERK/ERK ratios in the MAPK pathway indicated that increased concentrations of PM 2.5 can lead to lung inflammation.…”

Section: Discussionmentioning

confidence: 99%

Potential hazardous effects of printing room PM2.5 exposure include promotion of lung inflammation and subsequent injury

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There have been few studies investigating the potential effects of indoor sources of particulate matter on human health. in this study, the effect of different concentrations of fine particulate matter (PM 2.5) collected from a printing room on lung health was examined using cultured cells and a mouse model. Further, the mechanism of lung injury was examined. The results indicated that PM 2.5 significantly enhanced malondialdehyde activity (P<0.05), decreased superoxide dismutase activity (P<0.05), upregulated the expression of pro-inflammatory factors including interleukin (IL)-1β, tumor necrosis factor-, il-6 and downregulated the expression of the inflammatory factor IL-2 (P<0.05). Western blot analysis indicated that PM 2.5 significantly enhanced expression of phosphorylated (p)-ERK relative to total ERK, cyclooxygenase-2, p-anti-nuclear-factor-κB (p-NF-κB) relative to nF-κB, transforming growth factor-β1 and Bax relative to Bcl-2 in inflammation (P<0.05), fibrosis and apoptosis signaling pathways. Furthermore, the results revealed that exposure was associated with an increased abundance of pathogens including Burkholderiales, Coriobacteriia, and Betaproteobacteria in in the lungs. in conclusion, exposure to PM 2.5 from a printing room significantly increased inflammation, fibrosis, apoptosis and the abundance of pathogenic bacteria, indicating that exposure is potential threat to individuals who spend a significant amount of time in printing rooms.

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“…13 The effect of aflibercept in treating DME is not only based on VEGF inhibition alone but also on an anti-inflammatory mechanism of action, namely the inhibition of the recently described Placental growth factor (PlGF) and extracellular signal-regulated protein kinase (ERK) pathway. 14 Notably, all the above-mentioned studies were prospective randomized clinical trials (RCT) and featured the same treatment regimen, i.e. intravitreal anti-VEGF injections were given in fixed intervals.…”

Section: Introductionmentioning

confidence: 99%

<p>Two Year Visual Acuity and Structural Outcomes in Patients with Diabetic Macular Oedema Treated with Intravitreal Aflibercept – A Retrospective Cohort Study</p>

Kern¹,

Schiefelbein²,

Fu³

et al. 2020

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Purpose: To assess visual and anatomical outcomes of intravitreal aflibercept for clinically significant diabetic macular oedema (DME). Methods: For this retrospective single-center cohort study at a tertiary referral center, we performed a data warehouse query to identify 117 treatment-naive patients (139 eyes) undergoing intravitreal treatment with aflibercept for DME between January 2014 and May 2018. Changes in best-corrected visual acuity (BCVA) values (as measured with ETDRS letters), central retinal thickness (CRT) and total macular volume (TVOL) are reported over a two-year period at various time-points. Results: The total number of injections per study eye was 5.5 ± 1.4 after one and 8.7 ± 2.2 injections after two years. Baseline visual acuity (VA) was 60.1 ± 14.5 letters. A gain of 4.8 and 9.2 letters from baseline was observed after one and two years, respectively (both p ≤ 0.01). In comparison to the mean CRT at baseline (419 ± 174 µm), a CRT decrease was observed after one and two years of treatment (298 ± 115 µm and 319 ± 119 µm, respectively; both p ≤ 0.01). Similarly, TVOL decreased from 10.12 ± 2.05 mm 3 to 8.96 ± 0.96 mm 3 and 9.01 ± 1.29 mm 3 (both p ≤ 0.01). Conclusion: This study demonstrates that treating DME with intravitreal aflibercept yields positive functional and structural outcomes over a two-year period. However, we observed fewer injection numbers, along with inferior VA and structural outcomes than has been reported in randomized clinical trials. Our results show similar results as in patients treated with ranibizumab due to DME in real-life settings.

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Aflibercept regulates retinal inflammation elicited by high glucose via the PlGF/ERK pathway

Cited by 61 publications

References 50 publications

Stabilization of HIF-1α in Human Retinal Endothelial Cells Modulates Expression of miRNAs and Proangiogenic Growth Factors

Stabilization of HIF-1α in Human Retinal Endothelial Cells Modulates Expression of miRNAs and Proangiogenic Growth Factors

Potential hazardous effects of printing room PM2.5 exposure include promotion of lung inflammation and subsequent injury

<p>Two Year Visual Acuity and Structural Outcomes in Patients with Diabetic Macular Oedema Treated with Intravitreal Aflibercept – A Retrospective Cohort Study</p>

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