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Cell‐protective mechanisms of alpha 1 antitrypsin (A1AT) in the lung endothelium
Author(s) -
Lockett Angelia Denise,
Garrison Jana,
Kamocki Krzysztof,
Schweitzer Kelly,
Petrache Irina
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.1024.13
Subject(s) - tumor necrosis factor alpha , western blot , inflammation , endothelium , lung , apoptosis , endothelial stem cell , cell , in vivo , immunology , chemistry , medicine , biology , endocrinology , in vitro , biochemistry , microbiology and biotechnology , gene
Recent studies uncovered non‐cannonical functions of A1AT that lead to cellular protection from apoptosis and inflammation, including suppression of cigarette smoke (CS)‐induced increases in TNFα. We set out to investigate the mechanisms by which A1AT antagonizes TNFα?in vivo and in primary lung endothelial cell cultures. Mice were exposed to CS for up to 6 months and total lung RNA or protein was analyzed by real‐time PCR or Western blot, respectively. Primary rat lung microvascular cells were pretreated with A1AT, followed by studies of signaling and inflammatory responses in response to TNFα. Despite a decrease in the total lung TNFα message level (21 % at 16 weeks), both IκBα and MCP1 levels increased in CS‐exposed mice (1.7 fold + sem=.075; p=.05 and 1.4 fold +sem=.029; p<0.01, respectively). A1AT treatment increased basal IκBα?and delayed the IκBα?degradation induced by TNFα (10 ng/ml) in endothelial cells by 15 min. In conclusion, although TNFα message levels are not increased in smoked animals, the increased IκBα and MCP1 expression suggest that TNFα protein is activated by cigarette smoke. At the endothelial cell level, A1AT may alter TNFα signaling by regulating IκBα degradation. Understanding the anti‐inflammatory mechanisms of A1AT is important for developing therapeutic strategies against CS‐induced emphysema. Funded by: 1P50 HL084945