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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Physiol+Lung+Cell+Mol+Physiol
2016 ; 311
(5
): L913-L923
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Acrolein and thiol-reactive electrophiles suppress allergen-induced innate airway
epithelial responses by inhibition of DUOX1 and EGFR
#MMPMID27612966
Danyal K
; de Jong W
; O'Brien E
; Bauer RA
; Heppner DE
; Little AC
; Hristova M
; Habibovic A
; van der Vliet A
Am J Physiol Lung Cell Mol Physiol
2016[Nov]; 311
(5
): L913-L923
PMID27612966
show ga
Acrolein is a major thiol-reactive component of cigarette smoke (CS) that is
thought to contribute to increased asthma incidence associated with smoking.
Here, we explored the effects of acute acrolein exposure on innate airway
responses to two common airborne allergens, house dust mite and Alternaria
alternata, and observed that acrolein exposure of C57BL/6 mice (5 ppm, 4 h)
dramatically inhibited innate airway responses to subsequent allergen challenge,
demonstrated by attenuated release of the epithelial-derived cytokines IL-33,
IL-25, and IL-1?. Acrolein and other anti-inflammatory thiol-reactive
electrophiles, cinnamaldehyde, curcumin, and sulforaphane, similarly inhibited
allergen-induced production of these cytokines from human or murine airway
epithelial cells in vitro. Based on our previous observations indicating the
importance of Ca(2+)-dependent signaling, activation of the NADPH oxidase DUOX1,
and Src/EGFR-dependent signaling in allergen-induced epithelial secretion of
these cytokines, we explored the impact of acrolein on these pathways. Acrolein
and other thiol-reactive electrophiles were found to dramatically prevent
allergen-induced activation of DUOX1 as well as EGFR, and acrolein was capable of
inhibiting EGFR tyrosine kinase activity via modification of C797.
Biotin-labeling strategies indicated increased cysteine modification and
carbonylation of Src, EGFR, as well as DUOX1, in response to acrolein exposure in
vitro and in vivo, suggesting that direct alkylation of these proteins on
accessible cysteine residues may be responsible for their inhibition.
Collectively, our findings indicate a novel anti-inflammatory mechanism of
CS-derived acrolein and other thiol-reactive electrophiles, by directly
inhibiting DUOX1- and EGFR-mediated airway epithelial responses to airborne
allergens.