Prolastin, a pharmaceutical preparation of purified human α1-antitrypsin, blocks endotoxin-mediated cytokine release

Nita, Gelu M.; Hollander, Camilla; Westin, Ulla; Janciauskiene, Sabina-Marija

doi:10.1186/1465-9921-6-12

Cited by 72 publications

(51 citation statements)

References 59 publications

(59 reference statements)

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“…It is well accepted that AAT is functional in extracellular fluids by inhibition of proteinases. Recent studies have indicated that AAT can directly interact with various cells (9,13,21). In the present study, we have now shown that AAT can also enter cells and function intracellularly.…”

Section: Discussionsupporting

confidence: 69%

α1-Antitrypsin Protects β-Cells From Apoptosis

Lu²,

et al. 2007

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1␤-Cell apoptosis appears to represent a key event in the pathogenesis of type 1 diabetes. Previous studies have demonstrated that administration of the serine proteinase inhibitor ␣1-antitrypsin (AAT) prevents type 1 diabetes development in NOD mice and prolongs islet allograft survival in rodents; yet the mechanisms underlying this therapeutic benefit remain largely unclear. Herein we describe novel findings indicating that AAT significantly reduces cytokine-and streptozotocin (STZ)-induced ␤-cell apoptosis. Specifically, strong antiapoptotic activities for AAT (Prolastin, human) were observed when murine insulinoma cells (MIN6) were exposed to tumor necrosis factor-␣. In a second model system involving STZ-induced ␤-cell apoptosis, treatment of MIN6 cells with AAT similarly induced a significant increase in cellular viability and a reduction in apoptosis. Importantly, in both model systems, treatment with AAT completely abolished induced caspase-3 activity. In terms of its activities in vivo, treatment of C57BL/6 mice with AAT prevented STZ-induced diabetes and, in agreement with the in vitro analyses, supported the concept of a mechanism involving the disruption of ␤-cell apoptosis. These results propose a novel biological function for this molecule and suggest it may represent an effective candidate for attempts seeking to prevent or reverse type 1 diabetes. Diabetes 56:1316-1323, 2007 T ype 1 diabetes is an autoimmune disease resulting from destruction of the insulin-producing islet ␤-cells (1). Multiple lines of evidence indicate that antigen-presenting cells (APCs), especially dendritic cells, are pathologically active in orchestrating the process of insulitis (2). APCs within islets likely respond to micro-environmental triggers, including ␤-cell death and apoptosis, and initiate the insulitis process by migrating out of the islet and into the peripheral pancreatic lymph nodes. These APCs trigger the activation and proliferation of ␤-cell-reactive T-cells, which destroy islet cells at a rate that eventually results in type 1 diabetes. It has been shown that both direct cytotoxic (T-cell mediated) and indirect cytokine-dependent (e.g., interleukin-1, tumor necrosis factor-␣ [TNF-␣], and ␥-interferon) mechanisms are responsible for ␤-cell apoptosis (3).The direct cytotoxic mechanisms appear to involve the release of cytotoxic granule contents (e.g., perforin and granzymes) by cytotoxic T-cells (4). Granzymes play a critical role in triggering apoptotic cell death through mitochondrial pathways or by the activation of cellular caspases. Indeed, caspases (e.g., caspase-3) are key players in controlling the events leading to cellular apoptosis. Caspases are synthesized as inactive zymogens, which can be cleaved and activated by proteinases, including granzymes, cathepsins, and calpains. Granzymes and cathepsins are also members of a class of molecules known as serine proteinase inhibitor (serpin) proteinases. As for indirect mechanisms for ␤-cell apoptosis involving cytokines, signal transduction activities ...

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Section: Discussionsupporting

confidence: 69%

α1-Antitrypsin Protects β-Cells From Apoptosis

Lu²,

et al. 2007

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“…AAT inhibited lipopolysaccharide (LPS)-induced TNF-a and IL-1b release from monocytes dose-dependently and IL-8 release from neutrophils in vitro. Furthermore, AAT instillation after LPS challenge prevented LPS-induced IL-8 production in vivo [31]. Sputum protein and mRNA levels of IL-1b and TNF-a decreased significantly after AAT inhalation in the present CF patients.…”

Section: Discussionmentioning

confidence: 53%

“…Recent studies suggest a role for AAT as an anti-inflammatory modulator [31] independent of its antiprotease effect. AAT inhibited lipopolysaccharide (LPS)-induced TNF-a and IL-1b release from monocytes dose-dependently and IL-8 release from neutrophils in vitro.…”

Section: Discussionmentioning

confidence: 99%

1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients

Griese¹,

Latzin²,

Kappler³

et al. 2006

European Respiratory Journal

181

139

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The airways of cystic fibrosis (CF) patients are characterised by neutrophils that release high amounts of elastase overwhelming the local antiprotease shield. Inhalation of a 1 -antitrypsin (AAT) may restore the protease-antiprotease balance and attenuate airway inflammation in CF airways. The aims of the present study were: 1) to assess the best deposition region for inhaled AAT by two different inhalation strategies; and 2) to examine the effect of 4 weeks of AAT inhalation on lung function, protease-antiprotease balance and airway inflammation in CF patients.In a prospective, randomised study, 52 CF patients received a daily deposition by inhalation of 25 mg AAT for 4 weeks targeting their peripheral or bronchial compartment. The levels of elastase activity, AAT, pro-inflammatory cytokines, neutrophils, immunoglobulin G fragments and the numbers of Pseudomonas aeruginosa were assessed in induced sputum before and after the inhalation period.Inhalation of AAT increased AAT levels and decreased the levels of elastase activity, neutrophils, pro-inflammatory cytokines and the numbers of P. aeruginosa. However, it had no effect on lung function. No difference was found between the peripheral and bronchial inhalation mode.In conclusion, although no effect on lung function was observed, the clear reduction of airway inflammation after a 1 -antitrypsin treatment may precede pulmonary structural changes. The a 1 -antitrypsin deposition region may play a minor role for a 1 -antitrypsin inhalation in cystic fibrosis patients.

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“…In our experiments, A1AT decreased AFC to 12%, which is similar to the baseline value of Planes and colleagues (1). The structural properties that allow A1AT to inhibit proteases are susceptible to post-translational modifications by oxidation, nitration, and polymerization (49,50). Neutrophils and macrophages, which are capable of secreting high levels of oxidants at sites of inflammation, have been shown to oxidize two of the nine methionines in A1AT (358 and 351), leading to loss of antielastase activity (51).…”

Section: Discussionmentioning

confidence: 99%

α₁-Antitrypsin Inhibits Epithelial Na⁺ Transport In Vitro and In Vivo

Lazrak¹,

Nita²,

Subramaniyam³

et al. 2009

Am J Respir Cell Mol Biol

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A variety of studies have shown that Na 1 reabsorption across epithelial cells depends on the protease-antiprotease balance. Herein, we investigate the mechanisms by which a 1 -antitrypsin (A1AT), a major anti-serine protease in human plasma and lung epithelial fluid and lacking a Kunitz domain, regulates amiloridesensitive epithelial Na 1 channel (ENaC) function in vitro and in vivo. A1AT (0.05 mg/ml 5 1 mM) decreased ENaC currents across Xenopus laevis oocytes injected with human a,b,g-ENaC (hENaC) cRNAs, and human lung Clara-like (H441) cells expressing native ENaC, in a partially irreversible fashion. A1AT also decreased ENaC singlechannel activity when added in the pipette but not in the bath solutions of ENaC-expressing oocytes patched in the cell-attached mode. Incubation of A1AT with peroxynitrite (ONOO 2 ), an oxidizing and nitrating agent, abolished its antiprotease activity and significantly decreased its ability to inhibit ENaC. Intratracheal instillation of normal but not ONOO 2 -treated A1AT (1 mM) in C57BL/6 mice also decreased Na 1 -dependent alveolar fluid clearance to the same level as amiloride. Incubation of either H441 cells or ENaC-expressing oocytes with normal but not ONOO 2 -treated A1AT decreased their ability to cleave a substrate of serine proteases. A1AT had no effect on amiloride-sensitive currents of oocytes injected with hENaC bearing Liddle mutations, presumably because these channels remain at the surface longer than the wild-type channels. These data indicate that A1AT may be an important modulator of ENaC activity and of Na 1 -dependent fluid clearance across the distal lung epithelium in vivo by decreasing endogenous protease activity needed to activate silent ENaC.Keywords: alveolar fluid clearance; serine proteases; H441 cells; Xenopus oocytes; ENaCThe amiloride-sensitive epithelial Na 1 channels (ENaCs) play an important role in Na 1 and fluid homeostasis across a number of epithelial cells, including those in airway and alveolar spaces (1, 2). ENaC mRNA, protein levels, and ENaC activity are regulated by a variety of hormones (such as aldosterone and dexamethasone), second messengers cAMP/protein kinase A, and reactive intermediates (2-4). In addition, endogenous channelactivating proteases (CAPs), as well as proteases released by inflammatory cells (trypsin, elastase), activate ENaC either by cleaving critical amino acids in a-and g-ENaC subunits, or by activating signaling pathways (1, 2, 5-7).There has been considerable interest in identifying the mechanisms by which endogenous and exogenous proteases activate ENaC. Aprotinin, a potent and reversible Kunitz-type inhibitor of several serine proteases, including trypsin, plasmin, and kallikreins (8), has been reported to inhibit sodium transport among a variety of epithelial cells, including A6 (9), human bronchial epithelial (HBE) cells (10, 11), and rat and mouse lung alveolar epithelial cells (1). Other Kunitz-type serine protease inhibitors, such as hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2 (plac...

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Prolastin, a pharmaceutical preparation of purified human α1-antitrypsin, blocks endotoxin-mediated cytokine release

Cited by 72 publications

References 59 publications

α1-Antitrypsin Protects β-Cells From Apoptosis

α1-Antitrypsin Protects β-Cells From Apoptosis

1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients

α₁-Antitrypsin Inhibits Epithelial Na⁺ Transport In Vitro and In Vivo

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Prolastin, a pharmaceutical preparation of purified human α1-antitrypsin, blocks endotoxin-mediated cytokine release

Cited by 72 publications

References 59 publications

α1-Antitrypsin Protects β-Cells From Apoptosis

α1-Antitrypsin Protects β-Cells From Apoptosis

1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients

α1-Antitrypsin Inhibits Epithelial Na+ Transport In Vitro and In Vivo

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α₁-Antitrypsin Inhibits Epithelial Na⁺ Transport In Vitro and In Vivo