scholarly journals Nox4 Facilitates TGFβ1-Induced Fibrotic Response in Human Tenon’s Fibroblasts and Promotes Wound Collagen Accumulation in Murine Model of Glaucoma Filtration Surgery

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1126
Author(s):  
Manisha H. Shah ◽  
Elsa C. Chan ◽  
Nicole J. Van Bergen ◽  
Surinder S. Pandav ◽  
Sze Ng ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transforming Growth Factor ◽  
H2o2 Production ◽  
Induced Responses ◽  
Collagen Deposition ◽  
Surgical Wound ◽  
Filtration Surgery ◽  
Glaucoma Filtration Surgery ◽  
Collagen Production ◽  
Collagen Accumulation

Collagen accumulation in sub-conjunctival tissue at the surgical wound is one of the major complications associated with glaucoma filtration surgery (GFS). This process often leads to unwanted fibrotic scar formation at the lesion site and dysfunction of tissues. Previously, we demonstrated that NADPH oxidase 4 (Nox4) is implicated in transforming growth factor-beta (TGFβ)-induced collagen production in ocular fibroblasts and scarring responses in a mouse model of corneal injury. Here, we propose that Nox4 is an important facilitator of TGFβ-induced responses. We tested this hypothesis in human Tenon’s fibroblasts (HTF) and also assessed a role of Nox4 in an experimental mouse model of GFS. TGFβ1 induced Nox4 mRNA expression but downregulated Nox5 in HTF. Targeting Nox4 gene expression with an adenovirus carrying a Nox4 small interfering RNA (siRNA) (Ad-Nox4i) or removal of hydrogen peroxide (H2O2) with EUK-134 (25 μM) in HTFs significantly reduced TGFβ1-induced Nox4 expression, H2O2 production, and collagen synthesis (p < 0.05, n = 3–6). SIS3 (5 μM) that prevents Smad3 phosphorylation is found to suppress TGFβ1-induced collagen production in HTFs. Furthermore, Ad-Nox4i and EUK-134 both abolished TGFβ1-stimulated proliferation of HTFs. We also compared collagen deposition at the wound arising from GFS between wildtype (WT) and Nox4 knockout (KO) mice. Both collagen deposition and fibrovascularization at the wound were significantly decreased in Nox4 KO mice at 14 days after GFS. Our results provide comprehensive evidence that Nox4 is an important mediator for TGFβ1-induced responses in HTFs and collagen deposition in surgical wound following GFS in mice. As such, pharmacological inhibition of Nox4 would be a viable therapeutic strategy for the control of scarring after glaucoma surgery.

scholarly journals Integrin α5β1 Inhibition by CLT-28643 Reduces Postoperative Wound Healing in a Mouse Model of Glaucoma Filtration Surgery

2016 ◽  
Vol 57 (14) ◽  
pp. 6428 ◽  
Author(s):  
Tine Van Bergen ◽  
Grit Zahn ◽  
Patrizia Caldirola ◽  
Mario Fsadni ◽  
Ninus Caram-Lelham ◽  
...  
Keyword(s):  
Wound Healing ◽  
Mouse Model ◽  
Filtration Surgery ◽  
Integrin Α5β1 ◽  
Glaucoma Filtration Surgery ◽  
Postoperative Wound

Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells

2005 ◽  
Vol 289 (2) ◽  
pp. G342-G350 ◽  
Author(s):  
Shira Fruchtman ◽  
James G. Simmons ◽  
Carmen Z. Michaylira ◽  
Megan E. Miller ◽  
Christopher J. Greenhalgh ◽  
...  
Keyword(s):  
Wound Healing ◽  
Dna Synthesis ◽  
Cytokine Signaling ◽  
Type I ◽  
Collagen Deposition ◽  
Collagen Production ◽  
Collagen Accumulation ◽  
Igf I

Growth hormone (GH) and IGF-I play important roles in wound healing during intestinal injury and inflammation, but there is also indirect evidence that locally expressed IGF-I may act to induce excessive collagen deposition, which can lead to intestinal fibrosis. Factors that dictate the balance between normal wound healing and excessive healing responses are unknown. Using RNase protection assay and in situ hybridization, we determined whether GH and/or IGF-I increase type I collagen deposition in the intestine of rats fed by total parenteral nutrition (TPN), a feeding modality used for many patients following intestinal surgery and resection. We also used an in vitro model system to confirm our in vivo effects and to directly evaluate the relative potency of GH and IGF-I on DNA synthesis and collagen deposition in intestinal myofibroblasts. Both GH and IGF-I stimulated collagen production in vivo and in vitro, and IGF-I, but not GH, stimulated DNA synthesis in vitro. In collagen production, GH was less potent than IGF-I. Suppressors of cytokine signaling (SOC) are cytokine-inducible proteins that negatively feedback to inhibit the actions of cytokines and we recently found that GH selectively upregulates SOC-2 in the intestine of TPN-fed rats. We examined whether SOC-2 may be responsible for the difference in magnitude of action of GH and IGF-I on collagen accumulation. GH, but not IGF-I, induced SOC-2 in isolated myofibroblasts, and overexpression of SOC-2 led to a suppression of GH- and IGF-I-induced collagen accumulation. SOC-2 null mice infused with IGF-I showed greater collagen gene expression compared with wild-type (WT) mice. Myofibroblasts isolated from SOC-2 null mice showed increased IGF-I-stimulated DNA synthesis compared with WT cells. Taken together, these findings suggest that SOC-2 induced by GH may play an important role in suppressing collagen accumulation and mesenchymal cell proliferation induced by GH or GH-induced IGF-I, providing a mechanism for the differing potencies of GH and IGF-I on intestinal mesenchyme and collagen synthesis.

Development of novel therapeutics for glaucoma filtration surgery based on transforming growth factor-β receptor 1 inhibition

2019 ◽  
Vol 43 (48) ◽  
pp. 19265-19273
Author(s):  
Maja Zivkovic ◽  
Marko Zlatanovic ◽  
Nevena Zlatanovic ◽  
Mladjan Golubović ◽  
Aleksandar M. Veselinović
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Filtration Surgery ◽  
Qsar Modeling ◽  
Glaucoma Filtration Surgery ◽  
Computer Aided Drug Design ◽  
Novel Therapeutics ◽  
Computer Aided ◽  
Β Receptor

QSAR modeling with computer-aided drug design was used for the in silico development of novel therapeutics for glaucoma filtration surgery.

scholarly journals Potent and selective antisense oligonucleotides targeting the transforming growth factor beta (TGF-β) isoforms in advanced glaucoma: a preclinical evaluation

2016 ◽  
Vol 1 (2) ◽  
pp. 20-28
Author(s):  
Kathy Hasenbach ◽  
Tine Van Bergen ◽  
Evelien Vandewalle ◽  
Lies De Groef ◽  
Inge Van Hove ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Locked Nucleic Acid ◽  
Drug Candidate ◽  
Saline Control ◽  
Dependent Manner ◽  
Filtration Surgery ◽  
Glaucoma Filtration Surgery ◽  
Advanced Glaucoma

Purpose: ISARNA Therapeutics is developing highly potent and selective LNA-modified ASO gapmers targeting TGF-β1 and TGF-β2 mRNA. In the field of ophthalmology, glaucoma, the second leading cause for blindness in the US, has been linked to TGF-β activation as a key driver. ISTH0036 is a 14-mer phosphorothioate Locked Nucleic Acid- (LNA) modified antisense oligonucleotide gapmer, targeting the sequence of TGF-β2 mRNA and was developed for therapeutic intervention in ocular diseases. It was shown to effectively and potently downregulate target mRNA in a dose-dependent manner in relevant cell-based assays, as well as leading to target engagement in anterior eye segment tissues upon intravitreal administration (Isarna proprietary information). The aim of this study was to evaluate the therapeutic potential of ISTH0036 in murine models of glaucoma filtration surgery (GFS) following different intraocular administrations.Methods: A murine model of glaucoma filtration surgery has been used to evaluate the effect of intraocular ISTH0036 administration on post-operative wound healing. Bleb size and bleb survival were determined after different intraocular administrations of saline, control scrambled oligonucleotide or ISTH0036 (at day of surgery and after two weeks).Results: Intraocular administrations of ISTH0036 lead to a significant effect on bleb area and survival, as well as decreasing scarring (downregulation of collagen-1 and -3 fibers) in a murine glaucoma filtration surgery model.Conclusion: Consistent with the expected molecular mechanism of action and demonstrated pharmacokinetic (PK) and pharmacodynamic (PD) properties following intraocular administration, preclinical data with ISTH0036 in murine glaucoma filtration surgery model support the current exploration of the drug candidate in advanced glaucoma patients undergoing trabeculectomy.

scholarly journals SPARC Deficiency Results in Improved Surgical Survival in a Novel Mouse Model of Glaucoma Filtration Surgery

PLoS ONE ◽  
2010 ◽  
Vol 5 (2) ◽  
pp. e9415 ◽  
Author(s):  
Li-Fong Seet ◽  
Roseline Su ◽  
V. A. Barathi ◽  
Wing Sum Lee ◽  
Rebekah Poh ◽  
...  
Keyword(s):  
Mouse Model ◽  
Filtration Surgery ◽  
Glaucoma Filtration Surgery

Comparison of phaco time parameters in eyes with and without glaucoma filtration surgery due to pseudoexfoliation glaucoma

2021 ◽  
pp. 112067212110177
Author(s):  
Ayse Gul Kocak Altintas ◽  
Cagri Ilhan
Keyword(s):  
Clinical Characteristics ◽  
Pseudoexfoliation Glaucoma ◽  
Filtration Surgery ◽  
Glaucoma Filtration Surgery ◽  
Mean Values ◽  
Time Parameters ◽  
The Mean ◽  
Group 2 ◽  
Surgical Manipulations ◽  
Phaco Time

Purpose: To compare the phaco time parameters including ultrasound time (UST), effective phaco time (EPT), and average phaco power (APP) in eyes with pseudoexfoliation glaucoma (PEG) and had or had not glaucoma filtration surgery. Methods: In this retrospective comparative study, Group 1 was constructed with 84 PEG patients who had not operated previously, and Group 2 was constructed with 49 PEG patients who had glaucoma filtration surgery. The mean values of UST, EPT, and APP were compared. The preoperative clinical characteristics and surgical manipulations were also compared. Results: The mean ages and male-to-female ratios of the groups were similar ( p > 0.05, for both). There was no difference in the preoperative clinical characteristics, including biometric values between the groups ( p > 0.05, for all). Some surgical manipulations, including pupillary stretching ( p = 0.004), pupillary membrane peeling ( p = 0.021), iris hook using ( p = 0.041), and capsular tension ring implantation ( p = 0.041), were significantly performed more commonly in Group 2. Although the mean UST and EPT values were similar ( p > 0.05, for both), the mean APP value was significantly lower in Group 2 ( p = 0.011). Conclusion: The lower APP parameter was observed in PEG patients having had glaucoma filtration surgery. Needing more surgical manipulation to overcome poor pupillary dilation and weak zonular instability can be a reason for this result.

scholarly journals Prophylactic activity of cephalosporins in a mouse model of surgical wound infection.

1983 ◽  
Vol 36 (2) ◽  
pp. 161-166
Author(s):  
SARAH F. GRAPPEL ◽  
LILLIAN PHILLIPS ◽  
HUGH B. LEWIS ◽  
D. GWYN MORGAN ◽  
PAUL ACTOR
Keyword(s):  
Mouse Model ◽  
Wound Infection ◽  
Surgical Wound Infection ◽  
Surgical Wound
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