α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies

Ekeowa, Ugo I.; Gooptu, Bibek; Belorgey, Didier; Hägglöf, Peter; Karlsson-Li, Susanna; Miranda, Elena; Pérez, Juan; Ian, MacLeod; Kroger, Heike; Marciniak, Stefan J.; Crowther, Damian C.; Lomas, David A.

doi:10.1042/cs20080484

Cited by 52 publications

(55 citation statements)

References 181 publications

(199 reference statements)

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“…A1AT, a member of the serpin family of serine protease inhibitors, undergoes a marked conformational rearrangement upon binding and covalently inactivating its target proteases, suggesting that residues far from the reactive central loop ("C-loop") may contribute to its activity. Many mutations in A1AT outside the reactive C-loop lead to destabilization of the protein and multimerization, causing a collection of disorders known as serpinopathies (35). Despite the fact that K292 is not localized to a region with known functional significance, this residue also displays considerable variability across multiple crystal structures and may participate in a salt bridge with Glu288, suggesting a potentially important role in protein stabilization that would be blocked by lysine ε-acetylation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Quantitative assessment of the impact of the gut microbiota on lysine ε-acetylation of host proteins using gnotobiotic mice

Simón¹,

Cheng²,

Gordon³

2012

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

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The gut microbiota influences numerous aspects of human biology. One facet that has not been thoroughly explored is its impact on the host proteome. We hypothesized that the microbiota may produce certain of its effects through covalent modification of host proteins. We focused on protein lysine ε-acetylation because of its recently discovered roles in regulation of cell metabolism, and the potential for products of microbial fermentation to interact with the lysine acetylation machinery of host cells. Germ-free mice, fed a 15 N-labeled diet for two generations, were colonized as adults with a microbiota harvested from conventionally raised mouse donors. Using high-resolution mass spectrometry, we quantified 3,891 liver and proximal colonic proteins, 558 of which contained 1,602 sites of lysine acetylation, 43% not previously described. Multiple proteins from multiple subcellular compartments underwent microbiota-associated increases in their levels of lysine acetylation at one or more residues, in one or both tissues. Acetylated proteins were enriched in functions related to energy production, respiration, and primary metabolism. A number of the acetylation events affect lysine residues at or near the active sites of enzymes, whereas others occur at locations that may affect other facets of protein function. One of these modifications, affecting Lys292 in mouse α-1-antitrypsin, was detected in the corresponding lysine of the human serum protein. Methods described in this report can be applied to other co-or posttranslational modifications, and add quantitation of protein expression and covalent modification to the arsenal of techniques for characterizing the dynamic, important interactions between gut symbionts and their hosts.gut microbiome | quantitative proteomics | spirulina | stable isotopic labeling of mammals

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Section: Resultsmentioning

confidence: 99%

Quantitative assessment of the impact of the gut microbiota on lysine ε-acetylation of host proteins using gnotobiotic mice

Simón¹,

Cheng²,

Gordon³

2012

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

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“…COPD is characterized by progressive lung inflammation and irreversible narrowing of the airways. Three risk factors are associated with COPD: (i) cigarette smoking; (ii) heavy exposure to occupational and indoor air pollution; and (iii) alpha-1 antitrypsin deficiency (69,110). Available therapies for COPD include long-acting bronchodilators and at late stages, glucocorticoids.…”

Section: Nox2 As a Target For Drug Developmentmentioning

confidence: 99%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23,

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“…AAT deficiency (AATD) is a rare genetic disease caused by mutations in the AAT gene. There are two main phenotypes associated with this disease: (a) adult-onset emphysema due to loss of AAT activity and unchecked neutrophil elastase activity and (b) liver disease due to polymerization and retention of mutant AAT in liver (2)(3)(4)(5)(6)(7)(8)(9). The AAT mutation that causes the most severe lung and liver disease is the Glu342Lys (Z) point mutation.…”

Section: Introductionmentioning

confidence: 99%

Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin–related liver disease in mice

Guo¹,

Booten²,

Aghajan³

et al. 2013

J. Clin. Invest.

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Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease that results from mutations in the alpha-1 antitrypsin (AAT) gene. The mutant AAT protein aggregates and accumulates in the liver leading to AATD liver disease, which is only treatable by liver transplant. The PiZ transgenic mouse strain expresses a human AAT (hAAT) transgene that contains the AATD-associated Glu342Lys mutation. PiZ mice exhibit many AATD symptoms, including AAT protein aggregates, increased hepatocyte death, and liver fibrosis. In the present study, we systemically treated PiZ mice with an antisense oligonucleotide targeted against hAAT (AAT-ASO) and found reductions in circulating levels of AAT and both soluble and aggregated AAT protein in the liver. Furthermore, AAT-ASO administration in these animals stopped liver disease progression after short-term treatment, reversed liver disease after long-term treatment, and prevented liver disease in young animals. Additionally, antisense oligonucleotide treatment markedly decreased liver fibrosis in this mouse model. Administration of AAT-ASO in nonhuman primates led to an approximately 80% reduction in levels of circulating normal AAT, demonstrating potential for this approach in higher species. Antisense oligonucleotides thus represent a promising therapy for AATD liver disease.

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α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies

Cited by 52 publications

References 181 publications

Quantitative assessment of the impact of the gut microbiota on lysine ε-acetylation of host proteins using gnotobiotic mice

Quantitative assessment of the impact of the gut microbiota on lysine ε-acetylation of host proteins using gnotobiotic mice

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin–related liver disease in mice

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