Topical Timolol for a Refractory Wound

Tang, Jennifer; Dosal, Jacquelyn; Kirsner, Robert S.

doi:10.1111/j.1524-4725.2011.02200.x

Cited by 38 publications

(40 citation statements)

References 18 publications

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“…Norepinephrine, in particular, appears to be an important endogenous component of the stress-induced wound microenvironment. The presence and actions of catecholamines in the wound microenvironment is supported by reports of therapeutic success with the use of topical timolol, a beta-adrenergic receptor antagonist (Tang et al, 2012;Lev-Tov et al, 2013). Fully characterizing the B2AR autocrine pathway, and now, its newly discovered wound mediator, norepinephrine, may provide new insights into therapeutic approaches for improving healing.…”

Section: Discussionmentioning

confidence: 97%

Acute Wounding Alters the Beta2-Adrenergic Signaling and Catecholamine Synthetic Pathways in Keratinocytes

Sivamani

Shi

Griffiths

et al. 2014

Journal of Investigative Dermatology

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Keratinocyte migration is critical for wound re-epithelialization. Previous studies showed that epinephrine activates the beta2-adrenergic receptor (B2AR), impairing keratinocyte migration. Here, we investigated the keratinocyte catecholamine synthetic pathway in response to acute trauma. Cultured keratinocytes were scratch wounded and expression levels of the B2AR and catecholamine synthetic enzymes tyrosine hydroxylase and phenylethanolamine-N-methyltransferase were assayed. The binding affinity of the B2AR was measured. Wounding downregulated B2AR, tyrosine hydroxylase, and phenylethanolamine-N-methyltransferase expression, but pre-exposure to timolol, a beta-adrenergic receptor antagonist, delayed this effect. In wounded keratinocytes, B2AR-binding affinity remained depressed even after its expression returned to prewounding levels. Keratinocyte-derived norepinephrine increased after wounding. Norepinephrine impaired keratinocyte migration; this effect was abrogated with B2AR-selective antagonist ICI-118,551 but not with B1AR-selective antagonist bisoprolol. Finally, for clinical relevance, we determined that norepinephrine was present in freshly wounded skin, thus providing a potential mechanism for impaired healing by local B2AR activation in wound-edge keratinocytes. Taken together, the data show that keratinocytes modulate catecholamine synthetic enzymes and release norepinephrine after scratch wounding. Norepinephrine appears to be a stress-related mediator that impairs keratinocyte migration through activation of the B2AR. Future therapeutic strategies evaluating modulation of norepinephrine-related effects in the wound are warranted.

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Section: Discussionmentioning

confidence: 97%

Acute Wounding Alters the Beta2-Adrenergic Signaling and Catecholamine Synthetic Pathways in Keratinocytes

Sivamani

Shi

Griffiths

et al. 2014

Journal of Investigative Dermatology

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“…Next, we asked the question of whether blocking one of the receptors (β2‐ARs) could effectively increase cell migration and decrease IL‐6, both critical for improved healing. β‐Blockers are being used clinically to improve outcomes in burn wound patients [48, 49] and improve healing in chronic wounds [50, 51]. We selected the β1/2‐AR antagonist, Timolol, which has been shown to reverse β2‐AR inhibition of keratinocyte migration [32] and is a currently FDA‐approved drug.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, several studies have already reported that treatment with b2-AR blockers improves outcomes, such as decreased proinflammatory cytokine secretion and improved immune cell function, in patients who have endured an operative or traumatic injury [10,[83][84][85][86][87]. Improved healing in chronic skin wounds has also been reported using topical application of b-AR antagonists [50,88]. The mechanisms underlying the noted improved outcomes have only been partially explained.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk Between Adrenergic and Toll-Like Receptors in Human Mesenchymal Stem Cells and Keratinocytes: A Recipe for Impaired Wound Healing

Dasu

Ramírez

et al. 2014

Stem Cells Translational Medicine

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Previous studies demonstrate that skin wounds generate epinephrine (EPI) that can activate local adrenergic receptors (ARs), impairing healing. Bacterially derived activators of Toll-like receptors (TLRs) within the wound initiate inflammatory responses and can also impair healing. In this study, we examined the hypothesis that these two pathways crosstalk to one another, using EPI and macrophageactivating lipopeptide-2 (MALP2) to activate ARs and TLR2, respectively, in human bone marrowderived mesenchymal stem cells (BM-MSCs) and neonatal keratinocytes (NHKs). BM-MSCs exposed to EPI significantly (p < .05) increased TLR2 message (sevenfold BM-MSCs), TLR2 protein (twofold), and myeloid differentiation factor 88 (MyD88) (fourfold). Conversely, activation of TLR2 by MALP2 in these cells increased b2-AR message (twofold in BM-MSCs, 2.7-fold in NHKs), b2-AR protein (2.5-fold), phosphorylation of b-AR-activated kinase (p-BARK, twofold), and induced release of EPI from both cell types (twofold). Treating cells with EPI and MALP2 together, as would be encountered in a wound, increased b2-AR and p-BARK protein expression (sixfold), impaired cell migration (BM-MSCs-21%↓ and NHKs-60%↓, p < .002), and resulted in a 10-fold (BM-MSCs) and 51-fold (NHKs) increase in release of IL-6 (p < .001) responses that were remarkably reduced by pretreatment with b2-AR antagonists. In vivo, EPI-stressed animals exhibited impaired healing, with elevated levels of TLR2, MyD88, and IL-6 in the wounds (p < .05) relative to nonstressed controls. Thus, our data describe a recipe for decreasing cell migration and exacerbating inflammation via novel crosstalk between the adrenergic and Toll-like receptor pathways in BM-MSCs and NHKs. STEM CELLS TRANSLATIONAL MEDICINE 2014;3:745-759

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“…These findings prompted the authors to use timolol on a stalling venous leg ulcer that had failed multiple advanced treatments (Lev-Tov et al, 2013). Others (Braun et al, 2013;Manahan et al, 2014;Tang et al, 2012) have also reported cases of venous leg ulcers that have improved once a similar dosage of timolol was topically applied to the wound.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous work has also shown that catecholamines cross‐talk with Toll‐like receptors in both human MSC and keratinocytes to contribute to the chronic wound pathology (Dasu et al , ). In addition, we (Lev‐Tov et al , ) and others (Braun et al , ; Manahan et al , ; Tang et al , ) have also reported on the efficacy of timolol in improving healing of recalcitrant venous leg ulcers. Herein, we report success using a combination therapy of topical autologous, AMSC‐enriched high‐density lipoaspirate (HDL) and timolol, a beta‐adrenergic antagonist, to heal a venous ulcer.…”

Section: Introductionmentioning

confidence: 99%

Combination therapy of autologous adipose mesenchymal stem cell-enriched, high-density lipoaspirate and topical timolol for healing chronic wounds

Larsen

Tchanque-Fossuo

Gorouhi

et al. 2017

J Tissue Eng Regen Med

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Chronic venous leg ulcers are profoundly debilitating and result in billions in health care expenditure. Thus, there is a quest for engineered and innovative approaches. Herein we present a 63-year-old patient with a 30 year history of venous stasis and left lower extremity ulcers, which have been refractory to standard of care, anticoagulation and venous stripping. The medial ulcer was treated with transplantation of autologous adipose mesenchymal stem cell (AMSC)-enriched, high-density lipoaspirate (HDL) on OASIS wound matrix and compression therapy. The lateral ulcer was treated as a control with standard debridement and compression therapy. Four weeks later, both ulcers received daily topical timolol. Three months later, the test ulcer was completely epithelized and remains healed for over 15 months. However, the control showed minimal signs of improvement. In companion studies in our laboratory, human AMSC were cultured in Minimum Essential Medium Eagle Alpha Modifications (MEMα) with fetal bovine serum (FBS). Timolol was administered to AMSC prior to treatment with epinephrine and 104 bacteria/ml heat-killed Staphylococcus aureus. The MEMα with FBS devoid of AMSC served as a background control. After 24 h, cell culture supernatants and protein lysates were collected to determine cytokine production. There was a statistical significant decrease in pro-inflammatory interleukin-6 and -8 induced by the bacteria (to model the wound environment) in AMSC in the presence of timolol compared with control (p < 0.5). This is the first case of a successful combination of autologous AMSC-enriched, HDL with topical timolol for the healing of chronic venous leg ulcers. Copyright © 2016 John Wiley & Sons, Ltd.

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Topical Timolol for a Refractory Wound

Cited by 38 publications

References 18 publications

Acute Wounding Alters the Beta2-Adrenergic Signaling and Catecholamine Synthetic Pathways in Keratinocytes

Acute Wounding Alters the Beta2-Adrenergic Signaling and Catecholamine Synthetic Pathways in Keratinocytes

Crosstalk Between Adrenergic and Toll-Like Receptors in Human Mesenchymal Stem Cells and Keratinocytes: A Recipe for Impaired Wound Healing

Combination therapy of autologous adipose mesenchymal stem cell-enriched, high-density lipoaspirate and topical timolol for healing chronic wounds

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