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Effect of Cigarette Smoke Exposure and Structural Modifications on the α-1 Antitrypsin Interaction with Caspases

Overview of attention for article published in Molecular Medicine, January 2012
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Title
Effect of Cigarette Smoke Exposure and Structural Modifications on the α-1 Antitrypsin Interaction with Caspases
Published in
Molecular Medicine, January 2012
DOI 10.2119/molmed.2011.00207
Pubmed ID
Authors

Angelia D Lockett, Mary Van Demark, Yuan Gu, Kelly S Schweitzer, Ninotchka Sigua, Krzysztof Kamocki, Iwona Fijalkowska, Jana Garrison, Amanda J Fisher, Karina Serban, Robert A Wise, Terence R Flotte, Christian Mueller, Robert G Presson, Horia I Petrache, Rubin M Tuder, Irina Petrache

Abstract

α-1 Antitrypsin (A1AT) is a serpin with a major protective effect against cigarette smoke-induced emphysema development, and patients with mutations of the A1AT gene display a markedly increased risk for developing emphysema. We reported that A1AT protects lung endothelial cells from apoptosis and inhibits caspase-3 activity. It is not clear if cigarette smoking or A1AT mutations alter the caspase-3 inhibitory activity of A1AT and if this serpin alters the function of other caspases. We tested the hypothesis that the caspase-3 inhibitory activity of A1AT is impaired by cigarette smoking and that the A1AT RCL, the key antiprotease domain of the serpin, is required for its interaction with the caspase. We examined the caspase-3 inhibitory activity of human A1AT purified from plasma of actively smoking and nonsmoking individuals, either affected or unaffected with chronic obstructive pulmonary disease. We also tested the caspase inhibitory activity of two mutant forms of A1AT, the recombinant human piZZ and the RCL-deleted (RCL-null) A1AT forms. A1AT purified from the blood of active smokers exhibited marked attenuation in its caspase-3 inhibitory activity, independent of disease status. In vitro exposure of the normal (MM) form of A1AT to cigarette smoke extract reduced its ability to interact with caspase-3, measured by isothermal titration calorimetry, as did the deletion of the RCL, but not the ZZ point mutation. In cell-free assays A1AT was capable of inhibiting all executioner caspases, -3, -7 and especially -6, but not the initiator or inflammatory caspases. The inhibitory effect of A1AT against caspase-6 was tested in vivo, where overexpression of both human MM and ZZ-A1AT via adeno-associated virus transduction significantly protected against apoptosis and against airspace damage induced by intratracheal instillation of caspase-6 in mice. These data indicate a specific inhibitory effect of A1AT on executioner caspases, which is profoundly attenuated by active exposure to cigarette smoking and is dependent on the protein RCL, but is not affected by the PiZZ mutation.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 32 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Germany 1 3%
Canada 1 3%
Unknown 30 94%

Demographic breakdown

Readers by professional status Count As %
Researcher 6 19%
Student > Doctoral Student 5 16%
Student > Ph. D. Student 5 16%
Student > Master 5 16%
Student > Bachelor 3 9%
Other 6 19%
Unknown 2 6%
Readers by discipline Count As %
Medicine and Dentistry 12 38%
Biochemistry, Genetics and Molecular Biology 6 19%
Agricultural and Biological Sciences 3 9%
Veterinary Science and Veterinary Medicine 1 3%
Nursing and Health Professions 1 3%
Other 4 13%
Unknown 5 16%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 15 September 2012.
All research outputs
#8,039,089
of 12,819,611 outputs
Outputs from Molecular Medicine
#394
of 586 outputs
Outputs of similar age
#69,606
of 125,936 outputs
Outputs of similar age from Molecular Medicine
#7
of 9 outputs
Altmetric has tracked 12,819,611 research outputs across all sources so far. This one is in the 23rd percentile – i.e., 23% of other outputs scored the same or lower than it.
So far Altmetric has tracked 586 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.7. This one is in the 25th percentile – i.e., 25% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 125,936 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 33rd percentile – i.e., 33% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 9 others from the same source and published within six weeks on either side of this one. This one has scored higher than 2 of them.