{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:00:57Z","timestamp":1792011657923,"version":"4.4.0"},"reference-count":124,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Filtration bleb (FB) fibrosis represents the primary risk factor for glaucoma filtration surgery (GFS) failure. We reviewed the most recent literature on post-GFS fibrosis in humans, focusing on novel molecular pathways and antifibrotic treatments. Three main literature searches were conducted. First, we performed a narrative review of two models of extra-ocular fibrosis, idiopathic pulmonary fibrosis and skin fibrosis, to improve the comprehension of ocular fibrosis. Second, we conducted a systematic review of failed FB features in the PubMed, Embase, and Cochrane Library databases. Selected studies were screened based on the functional state and morphological features of FB. Third, we carried out a narrative review of novel potential antifibrotic molecules. In the systematic review, 11 studies met the criteria for analysis. Immunohistochemistry and genomics deemed SPARC and transglutaminases to be important for tissue remodeling and attributed pivotal roles to TGF\u03b2 and M2c macrophages in promoting FB fibrosis. Four major mechanisms were identified in the FB failure process: inflammation, fibroblast proliferation and myofibroblast conversion, vascularization, and tissue remodeling. On this basis, an updated model of FB fibrosis was described. Among the pharmacological options, particular attention was given to nintedanib, pirfenidone, and rapamycin, which are used in skin and pulmonary fibrosis, since their promising effects are demonstrated in experimental models of FB fibrosis. Based on the most recent literature, modern patho-physiological models of FB fibrosis should consider TGF\u03b2 and M2c macrophages as pivotal players and favorite targets for therapy, while research on antifibrotic strategies should clinically investigate medications utilized in the management of extra-ocular fibrosis.<\/jats:p>","DOI":"10.3390\/ijms26052327","type":"journal-article","created":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T11:20:57Z","timestamp":1741173657000},"page":"2327","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Fighting Bleb Fibrosis After Glaucoma Surgery: Updated Focus on Key Players and Novel Targets for Therapy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6399-3140","authenticated-orcid":false,"given":"Matteo","family":"Sacchi","sequence":"first","affiliation":[{"name":"Ophthalmology Unit, Azienda Ospedaliero-Universitaria di Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8386-9132","authenticated-orcid":false,"given":"Davide","family":"Tomaselli","sequence":"additional","affiliation":[{"name":"Ophthalmology Clinic, Alessandro Manzoni Hospital, ASST Lecco, 23900 Lecco, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5856-6686","authenticated-orcid":false,"given":"Maria Ludovica","family":"Ruggeri","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Imaging and Clinical Science, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Retina Division, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Bianca","family":"Aiello","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierfilippo","family":"Sabella","sequence":"additional","affiliation":[{"name":"Ophthalmology Clinic, Alessandro Manzoni Hospital, ASST Lecco, 23900 Lecco, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Dore","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Azienda Ospedaliero-Universitaria di Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3052-2662","authenticated-orcid":false,"given":"Antonio","family":"Pinna","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Azienda Ospedaliero-Universitaria di Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo","family":"Mastropasqua","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Imaging and Clinical Science, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Nubile","sequence":"additional","affiliation":[{"name":"Ophthalmology Clinic, Department of Medicine and Aging Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1625-6305","authenticated-orcid":false,"given":"Luca","family":"Agnifili","sequence":"additional","affiliation":[{"name":"Ophthalmology Clinic, Department of Medicine and Aging Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e053805","DOI":"10.1136\/bmjopen-2021-053805","article-title":"Time Trends, Associations and Prevalence of Blindness and Vision Loss Due to Glaucoma: An Analysis of Observational Data from the Global Burden of Disease Study 2017","volume":"12","author":"Sun","year":"2022","journal-title":"BMJ Open"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/aos.16618","article-title":"Incidence of Glaucoma Filtration Surgery from Disease Onset of Open-Angle Glaucoma","volume":"102","author":"Virtanen","year":"2024","journal-title":"Acta Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1007\/s00417-020-04671-2","article-title":"Structural Imaging of Conjunctival Filtering Blebs in XEN Gel Implantation and Trabeculectomy: A Confocal and Anterior Segment Optical Coherence Tomography Study","volume":"258","author":"Sacchi","year":"2020","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.ophtha.2006.01.062","article-title":"Trabeculectomy with Mitomycin C: Outcomes and Risk Factors for Failure in Phakic Open-Angle Glaucoma","volume":"113","author":"Fontana","year":"2006","journal-title":"Ophthalmology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"BIO114","DOI":"10.1167\/iovs.17-21795","article-title":"In Vivo Confocal Imaging of the Conjunctiva as a Predictive Tool for the Glaucoma Filtration Surgery Outcome","volume":"58","author":"Mastropasqua","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1165\/rcmb.2020-0182TR","article-title":"You Say You Want a Resolution (of Fibrosis)","volume":"63","author":"Atabai","year":"2020","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1172\/JCI93563","article-title":"Resolution of Organ Fibrosis","volume":"128","author":"Jun","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41584-019-0324-5","article-title":"Evasion of Apoptosis by Myofibroblasts: A Hallmark of Fibrotic Diseases","volume":"16","author":"Hinz","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1172\/JCI31487","article-title":"Common and Unique Mechanisms Regulate Fibrosis in Various Fibroproliferative Diseases","volume":"117","author":"Wynn","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/path.2277","article-title":"Cellular and Molecular Mechanisms of Fibrosis","volume":"214","author":"Wynn","year":"2008","journal-title":"J. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3770","DOI":"10.1172\/JCI94753","article-title":"Fibroblast-Specific TGF\u03b2-Smad2\/3 Signaling Underlies Cardiac Fibrosis","volume":"127","author":"Khalil","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"a021873","DOI":"10.1101\/cshperspect.a021873","article-title":"TGF\u03b2 and the TGF\u03b2 Family: Context-Dependent Roles in Cell and Tissue Physiology","volume":"8","author":"Morikawa","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1111\/aos.15098","article-title":"Preparing the Ocular Surface for Glaucoma Filtration Surgery: An Unmet Clinical Need","volume":"100","author":"Agnifili","year":"2022","journal-title":"Acta Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1007\/s00417-023-06333-5","article-title":"Managing the Ocular Surface after Glaucoma Filtration Surgery: An Orphan Topic","volume":"262","author":"Agnifili","year":"2023","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.exer.2015.03.021","article-title":"Conjunctival Fibrosis Following Filtering Glaucoma Surgery","volume":"142","author":"Schlunck","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1097\/ICU.0000000000000244","article-title":"A Role for Antimetabolites in Glaucoma Tube Surgery: Current Evidence and Future Directions","volume":"27","author":"Amoozgar","year":"2016","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1001\/archopht.1993.01090020117035","article-title":"Prolonged Localized Tissue Effects from 5-min Exposures to Fluorouracil and Mitomycin C","volume":"111","author":"Khaw","year":"1993","journal-title":"Arch. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6816","DOI":"10.1021\/cr3001059","article-title":"The Mitomycinoid Alkaloids: Mechanism of Action, Biosynthesis, Total Syntheses and Synthetic Approaches","volume":"113","author":"Bass","year":"2013","journal-title":"Chem. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Collotta, D., Colletta, S., Carlucci, V., Fruttero, C., Fea, A.M., and Collino, M. (2023). Pharmacological Approaches to Modulate the Scarring Process after Glaucoma Surgery. Pharmaceuticals, 16.","DOI":"10.3390\/ph16060898"},{"key":"ref_20","first-page":"1945","article-title":"A Review of the Efficacy of Mitomycin C in Glaucoma Filtration Surgery","volume":"9","author":"Aljasim","year":"2015","journal-title":"Clin. Ophthalmol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ang, B.C.H., Lim, S.Y., Betzler, B.K., Wong, H.J., Stewart, M.W., and Dorairaj, S. (2023). Recent Advancements in Glaucoma Surgery-A Review. Bioengineering, 10.","DOI":"10.3390\/bioengineering10091096"},{"key":"ref_22","first-page":"1975","article-title":"Transforming Growth Factor-Beta1, -Beta2, and -Beta3 in Vivo: Effects on Normal and Mitomycin C-Modulated Conjunctival Scarring","volume":"40","author":"Cordeiro","year":"1999","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"963","DOI":"10.3109\/02713689009069932","article-title":"Transforming Growth Factor-Beta in Human Aqueous Humor","volume":"9","author":"Jampel","year":"1990","journal-title":"Curr. Eye Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"CAT-152 0102 Trabeculectomy Study Group, Khaw, P., Grehn, F., Holl\u00f3, G., Overton, B., Wilson, R., Vogel, R., and Smith, Z. (2007). A Phase III Study of Subconjunctival Human Anti-Transforming Growth Factor Beta(2) Monoclonal Antibody (CAT-152) to Prevent Scarring after First-Time Trabeculectomy. Ophthalmology, 114, 1822\u20131830.","DOI":"10.1016\/j.ophtha.2007.03.050"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3273","DOI":"10.1007\/s00417-024-06476-z","article-title":"The Efficacy of Adjunctive Mitomycin C and\/or Anti-VEGF Agents on Glaucoma Tube Shunt Drainage Device Surgeries: A Systematic Review","volume":"262","author":"Figueiredo","year":"2024","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s00417-022-05785-5","article-title":"A Systematic Review and Meta-Analysis of Randomised Controlled Trials in the Management of Neovascular Glaucoma: Absence of Consensus and Variability in Practice","volume":"261","author":"Ramji","year":"2023","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1007\/BF00190712","article-title":"Histopathology of Episcleral Fibrosis after Trabeculectomy with and without Mitomycin C","volume":"234","author":"Mietz","year":"1996","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3835","DOI":"10.1167\/iovs.05-0960","article-title":"Potential Role of Tissue Transglutaminase in Glaucoma Filtering Surgery","volume":"47","author":"Priglinger","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1167\/iovs.08-2063","article-title":"Otago Glaucoma Surgery Outcome Study: The Pattern of Expression of MMPs and TIMPs in Bleb Capsules Surrounding Molteno Implants","volume":"50","author":"McCluskey","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1038\/eye.2008.330","article-title":"Increased Mast Cell Numbers in the Conjunctiva of Glaucoma Patients: A Possible Indicator of Preoperative Glaucoma Surgery Inflammation","volume":"23","author":"Chang","year":"2009","journal-title":"Eye"},{"key":"ref_32","first-page":"177","article-title":"SPARC Is Expressed in Scars of the Tenon\u2019s Capsule and Mediates Scarring Properties of Human Tenon\u2019s Fibroblasts in Vitro","volume":"17","author":"Fuchshofer","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Mahale, A., Fikri, F., Al Hati, K., Al Shahwan, S., Al Jadaan, I., Al Katan, H., Khandekar, R., Maktabi, A., and Edward, D.P. (2017). Histopathologic and Immunohistochemical Features of Capsular Tissue around Failed Ahmed Glaucoma Valves. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0187506"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/aos.12654","article-title":"Matrix Metalloproteinases (MMP-1, MMP-2, MMP-3 and MMP-9, and TIMP-1, TIMP-2 and TIMP-3) and Markers for Vascularization in Functioning and Non-Functioning Bleb Capsules of Glaucoma Drainage Implants","volume":"93","author":"Uusitalo","year":"2015","journal-title":"Acta Ophthalmol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1001\/jamaophthalmol.2017.3407","article-title":"Genotype-Phenotype Associations of IL6 and PRG4 With Conjunctival Fibrosis After Glaucoma Surgery","volume":"135","author":"Tagalakis","year":"2017","journal-title":"JAMA Ophthalmol."},{"key":"ref_36","first-page":"1521","article-title":"Absence of Lymphatic Vessels in Non-Functioning Bleb Capsules of Glaucoma Drainage Devices","volume":"35","author":"Siggel","year":"2020","journal-title":"Histol. Histopathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5644","DOI":"10.1038\/s41598-017-05780-5","article-title":"Genome-Wide RNA-Sequencing Analysis Identifies a Distinct Fibrosis Gene Signature in the Conjunctiva after Glaucoma Surgery","volume":"7","author":"Owen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mahale, A., Othman, M.W., Al Shahwan, S., Al Jadaan, I., Owaydha, O., Khan, Z., and Edward, D.P. (2015). Altered Expression of Fibrosis Genes in Capsules of Failed Ahmed Glaucoma Valve Implants. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122409"},{"key":"ref_39","first-page":"54","article-title":"Inflammation as an Orchestrator of Cutaneous Scar Formation: A Review of the Literature","volume":"7","author":"Wilgus","year":"2020","journal-title":"Plast. Aesthet. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"C1545","DOI":"10.1152\/ajpcell.00254.2023","article-title":"Fibrosis in Burns: An Overview of Mechanisms and Therapies","volume":"325","author":"Faour","year":"2023","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1146\/annurev-pathol-042320-030240","article-title":"Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis","volume":"17","author":"Moss","year":"2022","journal-title":"Annu. Rev. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2200957","DOI":"10.1183\/13993003.00957-2022","article-title":"Idiopathic Pulmonary Fibrosis: State of the Art for 2023","volume":"61","author":"Podolanczuk","year":"2023","journal-title":"Eur. Respir. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1097\/ACI.0000000000000775","article-title":"Comparison of Structural Components and Functional Mechanisms within the Skin vs. the Conjunctival Surface","volume":"21","author":"Valentine","year":"2021","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1097\/ACI.0000000000000842","article-title":"Comparison of Cytokine Mediators in Type 2 Inflammatory Conditions on the Skin and Ocular Surface","volume":"22","author":"Chen","year":"2022","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1089\/wound.2011.0357","article-title":"Mast Cells and Wound Healing","volume":"1","author":"Oskeritzian","year":"2012","journal-title":"Adv. Wound Care"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Wilgus, T.A., Ud-Din, S., and Bayat, A. (2020). A Review of the Evidence for and against a Role for Mast Cells in Cutaneous Scarring and Fibrosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249673"},{"key":"ref_47","first-page":"3596","article-title":"Mast Cell Chymase in Keloid Induces Profibrotic Response via Transforming Growth Factor-\u03921\/Smad Activation in Keloid Fibroblasts","volume":"7","author":"Dong","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/imm.13386","article-title":"ATP\/IL-33-Triggered Hyperactivation of Mast Cells Results in an Amplified Production of pro-Inflammatory Cytokines and Eicosanoids","volume":"164","author":"Jordan","year":"2021","journal-title":"Immunology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1089\/jir.2006.26.179","article-title":"Polarized Th2 Cytokine Production in Patients with Hypertrophic Scar Following Thermal Injury","volume":"26","author":"Tredget","year":"2006","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_50","first-page":"1","article-title":"The Role of Macrophages in Thermal Injury","volume":"12","author":"Penatzer","year":"2022","journal-title":"Int. J. Burns Trauma"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"tkac057","DOI":"10.1093\/burnst\/tkac057","article-title":"Epigenetic Regulation of Macrophage Polarization in Wound Healing","volume":"11","author":"Chen","year":"2023","journal-title":"Burns Trauma"},{"key":"ref_52","unstructured":"(2025, February 24). Ca2+ Influx Is an Essential Component of the Positive-Feedback Loop That Maintains Leading-Edge Structure and Activity in Macrophages|PNAS. Available online: https:\/\/www.pnas.org\/doi\/10.1073\/pnas.0707719104."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1038\/nature07577","article-title":"Calcium Flickers Steer Cell Migration","volume":"457","author":"Wei","year":"2009","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"25152564241291374","DOI":"10.1177\/25152564241291374","article-title":"Store-Operated Ca2+ Entry in Fibrosis and Tissue Remodeling","volume":"7","author":"Abdelnaby","year":"2024","journal-title":"Contact"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Roeb, E. (2023). Interleukin-13 (IL-13)-A Pleiotropic Cytokine Involved in Wound Healing and Fibrosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612884"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/j.1600-0625.2007.00550.x","article-title":"mTOR as a Potential Therapeutic Target for Treatment of Keloids and Excessive Scars","volume":"16","author":"Ong","year":"2007","journal-title":"Exp. Dermatol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s13555-016-0118-5","article-title":"5-Fluorouracil in the Treatment of Keloids and Hypertrophic Scars: A Comprehensive Review of the Literature","volume":"6","author":"Shah","year":"2016","journal-title":"Dermatol. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2950","DOI":"10.12659\/MSM.916305","article-title":"Intralesional Injection of Botulinum Toxin Type A Compared with Intralesional Injection of Corticosteroid for the Treatment of Hypertrophic Scar and Keloid: A Systematic Review and Meta-Analysis","volume":"25","author":"Bi","year":"2019","journal-title":"Med. Sci. Monit."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3349\/ymj.2013.54.2.437","article-title":"Rapamycin Inhibits Transforming Growth Factor \u03921-Induced Fibrogenesis in Primary Human Lung Fibroblasts","volume":"54","author":"Gao","year":"2013","journal-title":"Yonsei Med. J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1016\/j.cellsig.2009.07.016","article-title":"Rapamycin Induces the TGFbeta1\/Smad Signaling Cascade in Renal Mesangial Cells Upstream of mTOR","volume":"21","author":"Osman","year":"2009","journal-title":"Cell. Signal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrm3025","article-title":"mTOR: From Growth Signal Integration to Cancer, Diabetes and Ageing","volume":"12","author":"Zoncu","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1111\/j.1365-2443.2010.01482.x","article-title":"Activating Mutations of TOR (Target of Rapamycin)","volume":"16","author":"Hardt","year":"2011","journal-title":"Genes Cells"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/S0016-5085(99)70406-3","article-title":"Rapamycin Inhibits Hepatic Stellate Cell Proliferation in Vitro and Limits Fibrogenesis in an in Vivo Model of Liver Fibrosis","volume":"117","author":"Zhu","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1097\/SAP.0b013e31826956f6","article-title":"Transcriptional Profiling of Rapamycin-Treated Fibroblasts from Hypertrophic and Keloid Scars","volume":"72","author":"Wong","year":"2014","journal-title":"Ann. Plast. Surg."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1097\/DSS.0000000000000819","article-title":"Keloids and Hypertrophic Scars: Pathophysiology, Classification, and Treatment","volume":"43","author":"Berman","year":"2017","journal-title":"Dermatol. Surg."},{"key":"ref_66","first-page":"CD011642","article-title":"Laser Therapy for Treating Hypertrophic and Keloid Scars","volume":"9","author":"Leszczynski","year":"2022","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.amsu.2017.06.059","article-title":"Procedure, Applications, and Outcomes of Autologous Fat Grafting","volume":"20","author":"Simonacci","year":"2017","journal-title":"Ann. Med. Surg."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/ijd.15159","article-title":"Keloids: A Review of Therapeutic Management","volume":"60","author":"Ekstein","year":"2021","journal-title":"Int. J. Dermatol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Barratt, S.L., Creamer, A., Hayton, C., and Chaudhuri, N. (2018). Idiopathic Pulmonary Fibrosis (IPF): An Overview. J. Clin. Med., 7.","DOI":"10.3390\/jcm7080201"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s00408-022-00571-w","article-title":"Alveolar Epithelial Type 2 Cell Dysfunction in Idiopathic Pulmonary Fibrosis","volume":"200","author":"Zhu","year":"2022","journal-title":"Lung"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14532","DOI":"10.1038\/ncomms14532","article-title":"Cellular Senescence Mediates Fibrotic Pulmonary Disease","volume":"8","author":"Schafer","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1111\/febs.16573","article-title":"Context-Dependent Roles of Cellular Senescence in Normal, Aged, and Disease States","volume":"290","author":"Moiseeva","year":"2023","journal-title":"FEBS J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1164\/rccm.201810-1975TR","article-title":"Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases","volume":"200","author":"Barnes","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1164\/rccm.201904-0792OC","article-title":"Single-Cell Reconstruction of Human Basal Cell Diversity in Normal and Idiopathic Pulmonary Fibrosis Lungs","volume":"202","author":"Carraro","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"593283","DOI":"10.3389\/fcell.2020.593283","article-title":"Fibroblast Senescence in Idiopathic Pulmonary Fibrosis","volume":"8","author":"Lin","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_76","unstructured":"(2025, February 24). Ca2+ Signalling in Fibroblasts and the Therapeutic Potential of KCa3.1 Channel Blockers in Fibrotic Diseases\u2014PubMed, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/31758702\/."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"200269","DOI":"10.1183\/16000617.0269-2020","article-title":"The Promise of mTOR as a Therapeutic Target Pathway in Idiopathic Pulmonary Fibrosis","volume":"29","author":"Guillotin","year":"2020","journal-title":"Eur. Respir. Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ceb.2014.12.001","article-title":"mTOR Signaling in Cellular and Organismal Energetics","volume":"33","author":"Albert","year":"2015","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1111\/acel.12514","article-title":"mTORC1 Activation Decreases Autophagy in Aging and Idiopathic Pulmonary Fibrosis and Contributes to Apoptosis Resistance in IPF Fibroblasts","volume":"15","author":"Romero","year":"2016","journal-title":"Aging Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/crj.13466","article-title":"Idiopathic Pulmonary Fibrosis: Current and Future Treatment","volume":"16","author":"Glass","year":"2022","journal-title":"Clin. Respir. J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1111\/j.1440-1843.2011.01955.x","article-title":"Everolimus in IPF Study Investigators An Investigator-Driven Study of Everolimus in Surgical Lung Biopsy Confirmed Idiopathic Pulmonary Fibrosis","volume":"16","author":"Malouf","year":"2011","journal-title":"Respirology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.rmed.2017.07.062","article-title":"Therapeutic Targets in Idiopathic Pulmonary Fibrosis","volume":"131","author":"Kolb","year":"2017","journal-title":"Respir. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.pharmthera.2018.02.010","article-title":"Safer Approaches to Therapeutic Modulation of TGF\u03b2 Signaling for Respiratory Disease","volume":"187","author":"Lachapelle","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1136\/thoraxjnl-2019-214000","article-title":"Inhibition of Mast Cells: A Novel Mechanism by Which Nintedanib May Elicit Anti-Fibrotic Effects","volume":"75","author":"Miranda","year":"2020","journal-title":"Thorax"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1038\/s41433-020-1031-9","article-title":"The Control of Conjunctival Fibrosis as a Paradigm for the Prevention of Ocular Fibrosis-Related Blindness. \u201cFibrosis Has Many Friends\u201d","volume":"34","author":"Khaw","year":"2020","journal-title":"Eye"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.preteyeres.2017.08.001","article-title":"Myofibroblast Transdifferentiation: The Dark Force in Ocular Wound Healing and Fibrosis","volume":"60","author":"Shu","year":"2017","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Gajda-Dery\u0142o, B., Stahnke, T., Struckmann, S., Warsow, G., Birke, K., Birke, M.T., Hohberger, B., Rejdak, R., Fuellen, G., and J\u00fcnemann, A.G. (2019). Comparison of Cytokine\/Chemokine Levels in Aqueous Humor of Primary Open-Angle Glaucoma Patients with Positive or Negative Outcome Following Trabeculectomy. Biosci. Rep., 39.","DOI":"10.1042\/BSR20181894"},{"key":"ref_88","first-page":"66","article-title":"The Prognosis of Trabeculectomy in Primary Angle-Closure Glaucoma Patients","volume":"12","author":"Zhu","year":"2019","journal-title":"Int. J. Ophthalmol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"15308","DOI":"10.1016\/S0021-9258(18)98617-5","article-title":"Cross-Linking of Laminin-Nidogen Complexes by Tissue Transglutaminase. A Novel Mechanism for Basement Membrane Stabilization","volume":"266","author":"Aeschlimann","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3977","DOI":"10.1091\/mbc.e03-01-0001","article-title":"SPARC Inhibits Epithelial Cell Proliferation in Part through Stimulation of the Transforming Growth Factor-{beta}-Signaling System","volume":"14","author":"Schiemann","year":"2003","journal-title":"Mol. Biol. Cell"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1101\/gad.239327.114","article-title":"Rho-Actin Signaling to the MRTF Coactivators Dominates the Immediate Transcriptional Response to Serum in Fibroblasts","volume":"28","author":"Esnault","year":"2014","journal-title":"Genes Dev."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1186\/s13075-015-0877-x","article-title":"The Interaction of Lubricin\/Proteoglycan 4 (PRG4) with Toll-like Receptors 2 and 4: An Anti-Inflammatory Role of PRG4 in Synovial Fluid","volume":"17","author":"Alquraini","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1016\/j.ajpath.2011.07.032","article-title":"Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells","volume":"179","author":"Novince","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/gb-2006-7-5-216","article-title":"An Overview of the Serpin Superfamily","volume":"7","author":"Law","year":"2006","journal-title":"Genome Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"21.4.1","DOI":"10.1002\/0471140864.ps2104s24","article-title":"Metalloproteases","volume":"24","author":"Nagase","year":"2001","journal-title":"Curr. Protoc. Protein Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3488","DOI":"10.4049\/jimmunol.1101977","article-title":"Endogenous IL-33 Is Highly Expressed in Mouse Epithelial Barrier Tissues, Lymphoid Organs, Brain, Embryos, and Inflamed Tissues: In Situ Analysis Using a Novel Il-33-LacZ Gene Trap Reporter Strain","volume":"188","author":"Pichery","year":"2012","journal-title":"J. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1167\/iovs.17-22531","article-title":"Activation of the NFAT-Calcium Signaling Pathway in Human Lamina Cribrosa Cells in Glaucoma","volume":"59","author":"Irnaten","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrneph.2016.48","article-title":"TGF\u03b2: The Master Regulator of Fibrosis","volume":"12","author":"Meng","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1080\/08820538.2019.1687738","article-title":"Amyloidosis and Ocular Involvement: An Overview","volume":"35","author":"Dammacco","year":"2020","journal-title":"Semin. Ophthalmol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"12755","DOI":"10.1038\/s41598-023-40029-4","article-title":"Long-Term Surgical Results of Trabeculectomy for Secondary Glaucoma in Val30Met Hereditary Transthyretin Amyloidosis","volume":"13","author":"Kitahara","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1080\/13506129.2024.2398452","article-title":"Modified Ex-PRESS Technique versus Ahmed Glaucoma Valve as Primary Glaucoma Surgery for Hereditary Transthyretin Amyloidosis Glaucoma","volume":"31","author":"Vieira","year":"2024","journal-title":"Amyloid"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"100260","DOI":"10.1016\/j.mtbio.2022.100260","article-title":"Collecting and Deactivating TGF\u03921 Hydrogel for Anti-Scarring Therapy in Post-Glaucoma Filtration Surgery","volume":"14","author":"Wang","year":"2022","journal-title":"Mater. Today Bio"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1167\/iovs.64.10.2","article-title":"DPP-4 Inhibitors Attenuate Fibrosis After Glaucoma Filtering Surgery by Suppressing the TGF\u03b2\/Smad Signaling Pathway","volume":"64","author":"Yoshida","year":"2023","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.rmed.2018.12.015","article-title":"Inflammation and Immunity in IPF Pathogenesis and Treatment","volume":"147","author":"Heukels","year":"2019","journal-title":"Respir. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"109431","DOI":"10.1016\/j.exer.2023.109431","article-title":"The Anti-Scar Effect of Tyrosine-Kinase Inhibitor Nintedanib in Experimental Glaucoma Filtration Surgery in Rabbits","volume":"229","year":"2023","journal-title":"Exp. Eye Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1007\/s12325-023-02454-9","article-title":"A Narrative Review of Real-World Data on the Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis","volume":"40","author":"Podolanczuk","year":"2023","journal-title":"Adv. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1167\/tvst.12.11.21","article-title":"Inhibition of TGF\u03922-Induced Trabecular Meshwork Fibrosis by Pirfenidone","volume":"12","author":"Zhu","year":"2023","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3136","DOI":"10.1167\/iovs.10-6240","article-title":"Evaluation of Pirfenidone as a New Postoperative Antiscarring Agent in Experimental Glaucoma Surgery","volume":"52","author":"Zhong","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.jfo.2020.04.067","article-title":"The Effect of Halofug\u0131none and Pirfenidone on Wound Healing in Experimental Glaucoma Filtration Surgery","volume":"44","author":"Kasar","year":"2021","journal-title":"J. Fr. Ophtalmol."},{"key":"ref_110","first-page":"1477","article-title":"Pirfenidone Inhibits Fibrosis in Foreign Body Reaction after Glaucoma Drainage Device Implantation","volume":"10","author":"Jung","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1007\/s00417-015-3068-1","article-title":"Antifibrotic Effects of Pirfenidone on Tenon\u2019s Fibroblasts in Glaucomatous Eyes: Comparison with Mitomycin C and 5-Fluorouracil","volume":"253","author":"Na","year":"2015","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_112","first-page":"8411","article-title":"The Efficacy and Safety of Pirfenidone in the Treatment of HPS-Related Pulmonary Fibrosis and Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis","volume":"26","author":"Ma","year":"2022","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_113","first-page":"2191","article-title":"Pharmacokinetics of Pirfenidone after Topical Administration in Rabbit Eye","volume":"17","author":"Sun","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Stahnke, T., Siewert, S., Reske, T., Schmidt, W., Schmitz, K.-P., Grabow, N., Guthoff, R.F., and Wree, A. (2018). Development of a Biodegradable Antifibrotic Local Drug Delivery System for Glaucoma Microstents. Biosci. Rep., 38.","DOI":"10.1042\/BSR20180628"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Stahnke, T., Kowtharapu, B.S., Stachs, O., Schmitz, K.-P., Wurm, J., Wree, A., Guthoff, R.F., and Hovakimyan, M. (2017). Suppression of TGF\u03b2 Pathway by Pirfenidone Decreases Extracellular Matrix Deposition in Ocular Fibroblasts in Vitro. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172592"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1002\/jcp.24524","article-title":"Regulation of Plasticity and Fibrogenic Activity of Trabecular Meshwork Cells by Rho GTPase Signaling","volume":"229","author":"Pattabiraman","year":"2014","journal-title":"J. Cell. Physiol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/vop.12619","article-title":"Safety and Efficacy of Topically Applied 0.5% and 1% Pirfenidone in a Canine Model of Subconjunctival Fibrosis","volume":"22","author":"Westermeyer","year":"2019","journal-title":"Vet. Ophthalmol."},{"key":"ref_118","unstructured":"(2025, February 24). Targeting Ageing with Rapamycin and Its Derivatives in Humans: A Systematic Review\u2014The Lancet Healthy Longevity. Available online: https:\/\/www.thelancet.com\/journals\/lanhl\/article\/PIIS2666-7568(23)00258-1\/fulltext."},{"key":"ref_119","first-page":"54","article-title":"Inhibition by Rapamycin of PDGF- and bFGF-Induced Human Tenon Fibroblast Proliferation in Vitro","volume":"5","author":"Assalian","year":"1996","journal-title":"J. Glaucoma"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"108421","DOI":"10.1016\/j.exer.2020.108421","article-title":"Effects of Mammalian Target of Rapamycin Inhibitors on Fibrosis after Trabeculectomy","volume":"203","author":"Igarashi","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_121","first-page":"367","article-title":"The Suppression of Wound Healing Response with Sirolimus and Sunitinib Following Experimental Trabeculectomy in a Rabbit Model","volume":"41","author":"Eren","year":"2016","journal-title":"Curr. Eye Res."},{"key":"ref_122","first-page":"2495","article-title":"Anti-Proliferation Effects of Sirolimus Sustained Delivery Film in Rabbit Glaucoma Filtration Surgery","volume":"17","author":"Yan","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_123","first-page":"1389","article-title":"[Anti-scarring effect of rapamycin in rabbits following glaucoma filtering surgery]","volume":"38","author":"Kang","year":"2018","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao"},{"key":"ref_124","first-page":"1346","article-title":"[Anti-scarring effect of rapamycin following filtering surgery in rabbit eyes]","volume":"40","author":"Tai","year":"2020","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2327\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:47:46Z","timestamp":1760028466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2327"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,5]]},"references-count":124,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26052327"],"URL":"https:\/\/doi.org\/10.3390\/ijms26052327","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,5]]}}}