Enhanced Survival and Accelerated Perfusion of Skin Flap to Recipient Site Following Administration of Human α1-Antitrypsin in Murine Models

Schuster, Ronen; Bar-Nathan, Or; Tiosano, Alon; Lewis, Eli C.; Silberstein, Eldad

doi:10.1089/wound.2018.0889

Cited by 10 publications

(7 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At the same time, however, it should be noted that RT-PCR results in the present study show that the expression of IL-1β in wound explants is diminished by both hAAT formulations, while VEGF expression, a classic inflammatory downstream responder, is elevated. This is consistent with accelerated perfusion of skin flaps in hAAT-rich conditions [9] and upregulation of VEGF in angiogenesis studies that examine clinical-grade hAAT [34].…”

Section: Discussionsupporting

confidence: 77%

“…Human alpha1-antitrypsin (hAAT) is an endogenous circulating 52-kDa serine protease inhibitor, whose concentrations rise 4-6 fold during the acute inflammatory process. hAAT is mostly known in the context of hAAT deficiency, a genetic condition associated with early-onset pulmonary emphysema and necrotizing panniculitis, which is treated by weekly infusions of serum-purified hAAT [9,10]. However, evidence from recent decades has pointed to hAAT also being a potent anti-inflammatory, immunomodulatory, antibacterial and tissue-protective agent [11][12][13].…”

Section: Of 12mentioning

confidence: 99%

“…However, evidence from recent decades has pointed to hAAT also being a potent anti-inflammatory, immunomodulatory, antibacterial and tissue-protective agent [11][12][13]. Furthermore, recent animal studies demonstrate a protective effect for hAAT therapy in the context of multiple types of ischemia-reperfusion injuries [14,15], promoting re-vascularization alongside skin flap training [9].…”

Section: Of 12mentioning

confidence: 99%

See 2 more Smart Citations

Accelerated Wound Border Closure Using a Microemulsion Containing Non-Inhibitory Recombinant α1-Antitrypsin

Gimmon

Sherker

Kojukarov

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

Wound healing requires a non-compromising combination of inflammatory and anti-inflammatory processes. Human α1-antitrypsin (hAAT), a circulating glycoprotein that rises during acute-phase responses and during healthy pregnancies, is tissue-protective and tolerance-inducing; although anti-inflammatory, hAAT enhances revascularization. hAAT blocks tissue-degrading enzymes, including neutrophil elastase; it is, therefore, unclear how wound healing might improve under hAAT-rich conditions. Here, wound healing was examined in the presence of recombinant hAAT (hAATWT) and protease-inhibition-lacking hAAT (hAATCP). The impact of both hAAT forms was determined by an epithelial cell gap closure assay, and by excisional skin injuries via a microemulsion optimized for open wounds. Neutrophilic infiltration was examined after 8 h. According to results, both hAAT forms accelerated epithelial gap closure and excisional wound closure, particularly at early time points. Unlike dexamethasone-treated wounds, both resulted in closed borders at the 8-h time point. In untreated and hAATCP-treated wounds, leukocytic infiltrates were widespread, in hAATWT-treated wounds compartmentalized and in dexamethasone-treated wounds, scarce. Both hAAT forms decreased interleukin-1β and increased VEGF gene expression. In conclusion hAAT improves epithelial cell migration and outcomes of in vivo wounds irrespective of protease inhibition. While both forms of hAAT allow neutrophils to infiltrate, only native hAAT created discrete neutrophilic tissue clusters.

show abstract

Section: Discussionsupporting

confidence: 77%

Section: Of 12mentioning

confidence: 99%

Section: Of 12mentioning

confidence: 99%

See 1 more Smart Citation

Accelerated Wound Border Closure Using a Microemulsion Containing Non-Inhibitory Recombinant α1-Antitrypsin

Gimmon

Sherker

Kojukarov

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…So, skin flap surgery techniques were suggested to reduce the risks of arterial/venous occlusion and ischemia 25 . In addition, many therapeutic agents have been proven to enhance skin flap survival via the prevention of inflammation, providing free-radical scavenging, increasing angiogenesis, and/or enrichment of the microvascular network 27 .…”

Section: Discussionmentioning

confidence: 99%

Experimental study of the effects of nitroglycerin, botulinum toxin A, and clopidogrel on bipedicled superficial inferior epigastric artery flap survival

Ellabban

Elmasry

Abdelrahman

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Beneficial effects could be achieved by various agents such as nitroglycerin, botulinum toxin A (BoTA), and clopidogrel to improve skin flap ischaemia and venous congestion injuries. Eighty rats were subjected to either arterial ischaemia or venous congestion and applied to a bipedicled U-shaped superficial inferior epigastric artery (SIEA) flap with the administration of nitroglycerin, BoTA, or clopidogrel treatments. After 7 days, all rats were sacrificed for flap evaluation. Necrotic area percentage was significantly minimized in flaps treated with clopidogrel (24.49%) versus the ischemic flaps (34.78%); while nitroglycerin (19.22%) versus flaps with venous congestion (43.26%). With ischemia, light and electron microscopic assessments revealed that nitroglycerin produced degeneration of keratinocytes and disorganization of collagen fibers. At the same time, with clopidogrel administration, there was an improvement in the integrity of these structures. With venous congestion, nitroglycerin and BoTA treatments mitigated the epidermal and dermal injury; and clopidogrel caused coagulative necrosis. There was a significant increase in tissue gene expression and serum levels of vascular endothelial growth factor (VEGF) in ischemic flaps with BoTA and clopidogrel, nitroglycerin, and BoTA clopidogrel in flaps with venous congestion. With the 3 treatment agents, gene expression levels of tumor necrosis factor-α (TNF-α) were up-regulated in the flaps with ischemia and venous congestion. With all treatment modalities, its serum levels were significantly increased in flaps with venous congestion and significantly decreased in ischemic flaps. Our analyses suggest that the best treatment option for ischemic flaps is clopidogrel, while for flaps with venous congestion are nitroglycerin and BoTA.

show abstract

“…The most common use of hAAT is in the treatment of genetic hAAT deficiency, a disorder that causes early onset pulmonary emphysema, vasculitis, poor wound healing, and necrotizing panniculitis. 8,9 AAT is also a pro-resolution/inflammation-modulating, immunomodulatory, antibacterial, and tissue-protective molecule. [10][11][12] Animal studies have shown that hAAT therapy has a protective effect in various ischemia-reperfusion models and skin flap training, encouraging tissue restoration and revascularization.…”

Section: Introductionmentioning

confidence: 99%

Local Alpha1‐Antitrypsin Accelerates the Healing of Tympanic Membrane Perforation in Mice

El‐Saied,

Amar,

Kaplan

et al. 2024

The Laryngoscope

Self Cite

View full text Add to dashboard Cite

BackgroundMost tympanic membrane (TM) perforations heal spontaneously, but 10%–20% remain chronic and might lead to impaired hearing and recurrent middle ear infections. Alpha1‐antitrypsin (AAT) is a circulating tissue‐protective protein that is elevated under inflammatory conditions and is currently indicated for genetic AAT deficiency. Recently, AAT has been shown to promote tissue remodeling and inflammatory resolution.ObjectiveThis study aimed to examine the effects of local clinical‐grade AAT treatment on tissue repair in a mouse model of acute traumatic TM perforation.MethodsWild‐type mice underwent unilateral TM perforation and were either left untreated or treated locally with human AAT (9 × 10−3 mL at 20 mg/mL on days 0, 1, and 2; n = 15/group). The perforations were evaluated macroscopically on a serial basis. Mice were sacrificed on various days post‐injury, and TMs were excised for gene analysis by RT‐PCR.ResultsThere were no adverse reactions in hAAT‐treated ears throughout the study period. Compared with untreated animals, TM closure occurred earlier in the treated group (days until full closure, median: 4 and 9, respectively). According to gene expression analysis, VEGF, TGFβ, and collagen‐5A1 were induced earlier in AAT‐treated mice (day 4–5 compared with day 9). Additionally, IL‐10 expression levels were higher and IL‐6 levels were lower in treated versus untreated mice.ConclusionA local tissue environment rich in AAT promotes early tissue repair in a perforated TM model both macroscopically and molecularly. Studies are underway to examine TM functionality and recombinant AAT formulations for micro‐dosing in the format of a single local application.Level of EvidenceNA Laryngoscope, 2024

show abstract

Enhanced Survival and Accelerated Perfusion of Skin Flap to Recipient Site Following Administration of Human α1-Antitrypsin in Murine Models

Cited by 10 publications

References 40 publications

Accelerated Wound Border Closure Using a Microemulsion Containing Non-Inhibitory Recombinant α1-Antitrypsin

Accelerated Wound Border Closure Using a Microemulsion Containing Non-Inhibitory Recombinant α1-Antitrypsin

Experimental study of the effects of nitroglycerin, botulinum toxin A, and clopidogrel on bipedicled superficial inferior epigastric artery flap survival

Local Alpha1‐Antitrypsin Accelerates the Healing of Tympanic Membrane Perforation in Mice

Contact Info

Product

Resources

About