α-1 Antitrypsin Inhibits Caspase-3 Activity, Preventing Lung Endothelial Cell Apoptosis

Petrache, Irina; Fijałkowska, Iwona J.; Medler, Terry R.; Skirball, Jarrett; Cruz, Pedro; Zhen, Lijie; Petrache, Horia I.; Flotte, Terence R.; Tuder, Rubin M.

doi:10.2353/ajpath.2006.060058

Cited by 272 publications

(253 citation statements)

References 46 publications

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“…Stabilization of mitochondrial membranes and decreasing release of Ca++, cytochrome c, and other constituents may explain how AAT protects against induction of diabetes by the mitochondrial poison, streptozotocin (STZ) 9, 10. This effect, and inhibition of pro‐apoptotic signaling induced by tumor necrosis factor‐α (TNF‐α),10, 11 likely contribute to stabilization of pancreatic islet β‐cells and to the prevention/treatment of diabetes reported in animal models and in some human studies 12. Preservation of islets is of obvious interest in pancreas and islet transplantation (discussed in section 3.1, Pancreatic Islet Transplantation).…”

Section: Novel Functions Of Aatmentioning

confidence: 99%

“…Marcondes et al reported that AAT alters the cellular redox state and improves mitochondrial membrane potential while also increasing expression of antioxidant enzymes such as heme oxygenase 1 (Figure 1). 4, 5, 6, 7 Oxidative stress is important in inflammation and IRI, so these activities may contribute to the ability of AAT to promote cell and tissue survival and modulate inflammatory damage 10, 11, 13, 14, 15, 16, 17, 18, 19, 20. Because different types of lymphocytes, and cells in different activation states, differ in dependence on glycolysis vs oxidative phosphorylation, modulation of mitochondrial function may influence the balance between sensitization and tolerance 6…”

Section: Novel Functions Of Aatmentioning

confidence: 99%

“…AAT has been shown to inhibit apoptosis in multiple in vitro and in vivo models 10, 11, 13, 14, 15, 16, 17, 18, 19, 20. Increased cell survival may result not only from stabilization of mitochondrial membranes, but also likely involves direct inhibition of caspases (Figure 1).…”

Section: Novel Functions Of Aatmentioning

confidence: 99%

“…4, 5, 6, 7, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20 The molecular mechanism(s) of this inhibition have not been elucidated; caspases are cysteine proteases, while elastase and other canonical targets of AAT depend on serine. However, immunofluorescence studies have shown colocalization of AAT and activated caspase 3 in apoptotic but not in viable cells 11. Direct interactions between AAT and caspase 3 are also supported by co‐immunoprecipitation of AAT and caspase 3 by anti‐caspase antibodies and inhibition of enzymatic activity of purified caspase 3 by AAT in vitro 11.…”

Section: Novel Functions Of Aatmentioning

confidence: 99%

“…However, immunofluorescence studies have shown colocalization of AAT and activated caspase 3 in apoptotic but not in viable cells 11. Direct interactions between AAT and caspase 3 are also supported by co‐immunoprecipitation of AAT and caspase 3 by anti‐caspase antibodies and inhibition of enzymatic activity of purified caspase 3 by AAT in vitro 11. Furthermore, AAT has been reported to inhibit lung damage due to intratracheally administered purified caspase 3 11.…”

Section: Novel Functions Of Aatmentioning

confidence: 99%

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Alpha-1-antitrypsin in cell and organ transplantation

Berger

Liu

Uknis

et al. 2018

American Journal of Transplantation

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Limited availability of donor organs and risk of ischemia‐reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha‐1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor that limits inflammatory tissue damage. Purified plasma–derived AAT has been well tolerated in more than 30 years of use to prevent emphysema in AAT‐deficient individuals. Accumulating evidence suggests that AAT has additional anti‐inflammatory and tissue‐protective effects including improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting nuclear factor kappa B activation, modulating pro‐ vs anti‐inflammatory cytokine balance, and promoting immunologic tolerance. Cell culture and animal studies have shown that AAT limits tissue injury and promotes cell and tissue survival. AAT can promote tolerance in animal models by downregulating early inflammation and favoring induction and stabilization of regulatory T cells. The diverse intracellular and immune‐modulatory effects of AAT and its well‐established tolerability in patients suggest that it might be useful in transplantation. Clinical trials, planned and/or in progress, should help determine whether the promise of the animal and cellular studies will be fulfilled by improving outcomes in human organ transplantation.

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Section: Novel Functions Of Aatmentioning

confidence: 99%

Section: Novel Functions Of Aatmentioning

confidence: 99%

Section: Novel Functions Of Aatmentioning

confidence: 99%

Section: Novel Functions Of Aatmentioning

confidence: 99%

Section: Novel Functions Of Aatmentioning

confidence: 99%

See 3 more Smart Citations

Alpha-1-antitrypsin in cell and organ transplantation

Berger

Liu

Uknis

et al. 2018

American Journal of Transplantation

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Alpha-1-antitrypsin inhibits acute liver failure in mice

et al. 2014

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Acute liver failure remains a critical clinical condition, with high mortality rates, and increased apoptosis of hepatocytes represents a key event in the cause of liver failure. Alpha-1-antitrypsin (AAT) is synthesized and secreted mainly by hepatocytes, and plasma purified AAT is used for augmentation therapy in patients with AAT deficiency. Because AAT therapy exerts antiinflammatory and immune modulatory activities in various experimental models, and it was recently suggested that AAT exerts antiapoptotic activities, we aimed to explore whether administration of AAT may represent a therapeutic strategy to treat acute liver failure in mice. Well-established preclinical models of acute liver failure such as the Jo2 FAS/CD95 activating model and models of acetaminophen and aamanitin poisoning were used. Therapeutic effects of AAT were evaluated by monitoring animal survival, histopathological changes, measurement of caspase activity, and serum cytokine levels. Systemic treatment with AAT significantly decreased Jo2-induced liver cell apoptosis and prolonged survival of mice. Native and oxidized (lacking elastase inhibitory activity) forms of AAT were equally effective in preventing acute liver injury and showed direct inhibition of active caspase-3 and 28 in liver homogenates and in a cell-free system in vitro. Concomitantly, mice treated with AAT showed significantly lower serum levels of tumor necrosis factor alpha (TNF-a), which also paralleled the reduced activity of ADAM17 (TACE). Noticeably, the increased survival and a reduction of apoptotic hepatocytes were also observed in the a-amanitin and acetaminophen-induced liver injury mouse models. Conclusion: Our data suggest that systemic administration of AAT can be a promising therapy to treat acute liver failure and clinical studies to explore this treatment in humans should be initiated. (HEPATOLOGY 2014;59:2299-2308

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

El‐Saied,

Amar,

Kaplan

et al. 2024

The Laryngoscope

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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

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α-1 Antitrypsin Inhibits Caspase-3 Activity, Preventing Lung Endothelial Cell Apoptosis

Cited by 272 publications

References 46 publications

Alpha-1-antitrypsin in cell and organ transplantation

Alpha-1-antitrypsin in cell and organ transplantation

Alpha-1-antitrypsin inhibits acute liver failure in mice

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

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