Treatment of Chronic Leg Ulcers With Topical Activated Protein C

Whitmont, Kaley; Reid, Ian A.; Tritton, Sara M.; March, Lyn; Xue, Meilang; Lee, Michael; Fulcher, Greg; Sambrook, Phil; Slobedman, Eric; Cooper, Alan; Jackson, Chris

doi:10.1001/archderm.144.11.1479

Cited by 44 publications

(57 citation statements)

References 12 publications

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“…A clinical study of four patients found that treatment of chronic leg ulcers with topical aPC stimulated wound healing by activating skin reepithelialization (27). Furthermore, the local aPC treatment was well tolerated, with no adverse effects or complications (27). Consistent with these findings, our in vivo studies demonstrated the capacity of aPC treatment to favor mucosal healing.…”

Section: Discussionsupporting

confidence: 80%

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Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Vetrano

Ploplis

Sala

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The protein C (PC) pathway is a well-characterized coagulation system. Endothelial PC receptors and thrombomodulin mediate the conversion of PC to its activated form, a potent anticoagulant and anti-inflammatory molecule. Here we show that the PC pathway is expressed on intestinal epithelial cells. The epithelial expression of PC and endothelial PC receptor is down-regulated In patients with inflammatory bowel disease. PC −/− /PC(Tg) mice, expressing only 3% of WT PC, developed spontaneous intestinal inflammation and were prone to severe experimental colitis. These mice also demonstrated spontaneous elevated production of inflammatory cytokines and increased intestinal permeability. Structural analysis of epithelial tight junction molecules revealed that lack of PC leads to decreased JAM-A and claudin-3 expression and an altered pattern of ZO-1 expression. In vitro, treatment of epithelial cells with activated PC led to protection of tight junction disruption induced by TNF-α, and in vivo, topical treatment with activated PC led to mucosal healing and amelioration of colitis. Taken together, these findings demonstrate that the PC pathway is a unique system involved in controlling intestinal homeostasis and inflammation by regulating epithelial barrier function.

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Section: Discussionsupporting

confidence: 80%

“…Thus, topical administration of aPC could promote mucosal healing. A clinical study of four patients found that treatment of chronic leg ulcers with topical aPC stimulated wound healing by activating skin reepithelialization (27). Furthermore, the local aPC treatment was well tolerated, with no adverse effects or complications (27).…”

Section: Discussionmentioning

confidence: 99%

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Vetrano

Ploplis

Sala

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…14,74,117 On the basis of preclinical data showing APC benefits for I/R injury to the brain, 64 Kamei and colleagues initiated ongoing open-label studies of wt-APC administered directly by injection into the eye for ischemic retinal injury, which appear promising 118 and should lead to double-blind studies to clarify the real benefits of APC therapy for the ischemic damage to the retina.…”

Section: Wt-apc: Studies Of Wound Healing and Ischemic Retinal Injurymentioning

confidence: 99%

Activated protein C: biased for translation

Griffin

Zloković

Mosnier

2015

Blood

223

320

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The homeostatic blood protease, activated protein C (APC), can function as (1) an antithrombotic on the basis of inactivation of clotting factors Va and VIIIa; (2) a cytoprotective on the basis of endothelial barrier stabilization and anti-inflammatory and antiapoptotic actions; and (3) a regenerative on the basis of stimulation of neurogenesis, angiogenesis, and wound healing. Pharmacologic therapies using recombinant human and murine APCs indicate that APC provides effective acute or chronic therapies for a strikingly diverse range of preclinical injury models. APC reduces the damage caused by the following: ischemia/reperfusion in brain, heart, and kidney; pulmonary, kidney, and gastrointestinal inflammation; sepsis; Ebola virus; diabetes; and total lethal body radiation. For these beneficial effects, APC alters cell signaling networks and gene expression profiles by activating protease-activated receptors 1 and 3. APC’s activation of these G protein–coupled receptors differs completely from thrombin’s activation mechanism due to biased signaling via either G proteins or β-arrestin-2. To reduce APC-associated bleeding risk, APC variants were engineered to lack >90% anticoagulant activity but retain normal cell signaling. Such a neuroprotective variant, 3K3A-APC (Lys191-193Ala), has advanced to clinical trials for ischemic stroke. A rich data set of preclinical knowledge provides a solid foundation for potential translation of APC variants to future novel therapies.

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“…In fact, a recombinant form of human activated protein C (Drotrecogin alfa activated; commercially known as Xigris; Lilly Deutschland, Bad Homburg, Germany) was approved in 2001 by the U.S. Food and Drug Administration for the treatment of severe sepsis and high risk of death (7). Although the precise way of action has not yet been elucidated (5,8), the immunosuppressive and cytoprotective effects of activated protein C now emerge as a potential treatment for a number of other diseases that are associated with excessive immune responses such as acute respiratory distress syndrome, multiple sclerosis, rheumatoid arthritis, brain injury, stroke, and chronic wounds (9)(10)(11)(12). A recent study reported that activated protein C was also effective in protecting against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis, where it modulates the mitochondrial apoptosis pathway via the protease-activated receptor-1 (PAR-1) and the endothelial protein C receptor (EPCR) (13).…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

Activated Protein C Attenuates Systemic Lupus Erythematosus and Lupus Nephritis in MRL-Fas(lpr) Mice

Lichtnekert

Rupanagudi

Kulkarni

et al. 2011

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease leading to inflammatory tissue damage in multiple organs (e.g., lupus nephritis). Current treatments including steroids, antimalarials, and immunosuppressive drugs have significant side effects. Activated protein C is a natural protein with anticoagulant and immunomodulatory effects, and its recombinant version has been approved by the U.S. Food and Drug Administration to treat severe sepsis. Given the similarities between overshooting immune activation in sepsis and autoimmunity, we hypothesized that recombinant activated protein C would also suppress SLE and lupus nephritis. To test this concept, autoimmune female MRL-Fas(lpr) mice were injected with either vehicle or recombinant human activated protein C from week 14–18 of age. Activated protein C treatment significantly suppressed lupus nephritis as evidenced by decrease in activity index, glomerular IgG and complement C3 deposits, macrophage counts, as well as intrarenal IL-12 expression. Further, activated protein C attenuated cutaneous lupus and lung disease as compared with vehicle-treated MRL-Fas(lpr) mice. In addition, parameters of systemic autoimmunity, such as plasma cytokine levels of IL-12p40, IL-6, and CCL2/MCP-1, and numbers of B cells and plasma cells in spleen were suppressed by activated protein C. The latter was associated with lower total plasma IgM and IgG levels as well as lower titers of anti-dsDNA IgG and rheumatoid factor. Together, recombinant activated protein C suppresses the abnormal systemic immune activation in SLE of MRL-Fas(lpr) mice, which prevents subsequent kidney, lung, and skin disease. These results implicate that recombinant activated protein C might be useful for the treatment of human SLE.

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Treatment of Chronic Leg Ulcers With Topical Activated Protein C

Cited by 44 publications

References 12 publications

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation

Activated protein C: biased for translation

Activated Protein C Attenuates Systemic Lupus Erythematosus and Lupus Nephritis in MRL-Fas(lpr) Mice

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