Ocular Fibroblast Diversity: Implications for Inflammation and Ocular Wound Healing

Xia, Xi; McMillan, David H.; Lehmann, Geniece M.; Sime, Patricia J.; Libby, Richard T.; Huxlin, Krystel R.; Feldon, Steven E.; Phipps, Richard P.

doi:10.1167/iovs.10-7066

Cited by 44 publications

(35 citation statements)

References 32 publications

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“…Cell culture supernatants were collected at the conclusion of each experiment. IL-6, IL-8, and MCP-1 were detected in the supernatants by ELISA as previously described (48). IL-6 antibodies were purchased from BD Pharmingen (554543 and 554546, San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Attenuation of inflammatory mediator production by the NF-κB member RelB is mediated by microRNA-146a in lung fibroblasts

McMillan

Woeller

Thatcher

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lung inflammation can result from exposure to multiple types of inflammatory stimuli. Fibroblasts, key structural cells in the lung that are integral to inflammation and wound healing, produce inflammatory mediators after exposure to stimuli such as IL-1β. We and others have shown that the NF-κB member RelB has anti-inflammatory properties in mice. Little is known, however, about the anti-inflammatory role of RelB in human cells and how it functions. MicroRNAs (miRNAs), a novel class of small, noncoding RNAs, can mediate inflammatory signaling pathways, including NF-κB, through regulation of target gene expression. Our goal was to analyze the anti-inflammatory properties of RelB in human lung fibroblasts. We hypothesized that RelB regulates inflammatory mediator production in lung fibroblasts in part through a mechanism involving miRNAs. To accomplish this, we transfected human lung fibroblasts with a plasmid encoding RelB and small interfering (si)RNA targeting RelB mRNA to overexpress and downregulate RelB, respectively. IL-1β, a powerful proinflammatory stimulus, was used to induce NF-κB-driven inflammatory responses. RelB overexpression reduced IL-1β-induced cyclooxygenase (Cox)-2, PGE₂, and cytokine production, and RelB downregulation increased Cox-2 expression and PGE₂ production. Furthermore, RelB overexpression increased IL-1β-induced expression of miRNA-146a, an NF-κB-dependent miRNA with anti-inflammatory properties, whereas RelB downregulation reduced miRNA-146a. miR-146a overexpression ablated the effects of RelB downregulation on IL-1β-induced Cox-2, PGE₂, and IL-6 production, suggesting that RelB mediates IL-1β-induced inflammatory mediator production in lung fibroblasts through miRNA-146a. RelB and miRNA-146a may therefore be new therapeutic targets in the treatment of lung inflammation caused by various agents and conditions.

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Section: Methodsmentioning

confidence: 99%

Attenuation of inflammatory mediator production by the NF-κB member RelB is mediated by microRNA-146a in lung fibroblasts

McMillan

Woeller

Thatcher

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…-27 -populations of ocular fibroblasts and keratocytes Wilson et al, 2004;Xi et al, 2011). In other eye locations and during subsequent stages of cornea repair , intercellular crosstalk between myofibroblast precursors and inflammatory cells is likely as important as described for various organs (Borthwick et al, 2013;Brancato and Albina, 2011;Eming et al, 2007;Martin and Leibovich, 2005;Mosser and Edwards, 2008;Wynn et al, 2013;Wynn and Ramalingam, 2012).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 97%

Myofibroblasts

Hinz¹

2016

Experimental Eye Research

354

341

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Myofibroblasts are activated in response to tissue injury with the primary task to repair lost or damaged extracellular matrix. Enhanced collagen secretion and subsequent contraction - scarring - are part of the normal wound healing response and crucial to restore tissue integrity. Due to myofibroblasts ability to repair but not regenerate, accumulation of scar tissue is always associated with reduced organ performance. This is a fair price to pay by the body for not falling apart. Whereas myofibroblasts typically vanish after successful repair, dysregulation of the normal repair process can lead to persistent myofibroblast activation, for instance by chronic inflammation or mechanical stress in the tissue. Excessive repair leads to the accumulation of stiff collagenous ECM contractures - fibrosis - with dramatic consequences for organ function. The clinical need to terminate detrimental myofibroblast activities has stimulated researchers to answer a number of essential questions: where do myofibroblasts come from, what are the factors leading to their activation, how do we discriminate myofibroblasts from other cells, what is the molecular basis for their contractile activity, and how can we stop or at least control them? This article reviews the current state of the myofibroblast literature by emphasizing their role in ocular repair and fibrosis. It appears that although the eye is quite an extraordinary organ, ocular myofibroblasts behave or misbehave just like their siblings in other organs.

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“…Human Tenon fibroblasts undergo a cascade of cellular and biochemical events involving the activation, migration, and proliferation of these cells, together with the deposition of new extracellular matrix and scar formation. 18 This healing response may be more aggressive in children and young adults. 19 Surgical results of trabeculectomy in the pediatric age group are frequently disappointing.…”

Section: Discussionmentioning

confidence: 99%

Excision of Tenon Capsule in Pediatric Trabeculectomy

Awadein

Sayed

2016

Journal of Glaucoma

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Ocular Fibroblast Diversity: Implications for Inflammation and Ocular Wound Healing

Abstract: The results highlight the inherent differences between ocular fibroblast strains and provide crucial insight into novel, tissue-specific treatments for ocular inflammation and disease, such as RelB overexpression.

Cited by 44 publications

References 32 publications

Attenuation of inflammatory mediator production by the NF-κB member RelB is mediated by microRNA-146a in lung fibroblasts

Attenuation of inflammatory mediator production by the NF-κB member RelB is mediated by microRNA-146a in lung fibroblasts

Myofibroblasts

Excision of Tenon Capsule in Pediatric Trabeculectomy

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