Susceptibility for cigarette smoke-induced DAMP release and DAMP-induced inflammation in COPD.
Cigarette smoke (CS) exposure is a major risk factor for chronic obstructive pulmonary disease (COPD). We investigated whether CS-induced damage-associated molecular pattern (DAMP) release or DAMP-mediated inflammation contributes to susceptibility for COPD. Samples, including bronchial brushings, were collected from young and old individuals, susceptible and nonsusceptible for the development of COPD, before and after smoking, and used for gene profiling and airway epithelial cell (AEC) culture. AECs were exposed to CS extract (CSE) or specific DAMPs. BALB/cByJ and DBA/2J mice were intranasally exposed to LL-37 and mitochondrial (mt)DAMPs. Functional gene-set enrichment analysis showed that CS significantly increases the airway epithelial gene expression of DAMPs and DAMP receptors in COPD patients. In cultured AECs, we observed that CSE induces necrosis and DAMP release, with specifically higher galectin-3 release from COPD-derived compared with control-derived cells. Galectin-3, LL-37, and mtDAMPs increased CXCL8 secretion in AECs. LL-37 and mtDAMPs induced neutrophilic airway inflammation, exclusively in mice susceptible for CS-induced airway inflammation. Collectively, we show that in airway epithelium from COPD patients, the CS-induced expression of DAMPs and DAMP receptors in vivo and the release of galectin-3 in vitro is exaggerated. Furthermore, our studies indicate that a predisposition to release DAMPs and subsequent induction of inflammation may contribute to the development of COPD.
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; s.d.pouwels@umcg.nl.|University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands; and.
Simon D
SD
Pouwels
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands; and.
Laura
L
Hesse
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands; and.
Alen
A
Faiz
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Jaap
J
Lubbers
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Priya K
PK
Bodha
University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands; and.|Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Nick H T
NH
Ten Hacken
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands; and.
Antoon J M
AJ
van Oosterhout
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands; and.
Martijn C
MC
Nawijn
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands; and.|Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Irene H
IH
Heijink
D000281:Administration, Intranasal; D000328:Adult; D000067531:Alarmins / Q000378:metabolism*; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000097:blood; D016923:Cell Death; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000473:pathology; D037502:Galectin 3 / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D016209:Interleukin-8 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008928:Mitochondria / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D012907:Smoking / Q000009:adverse effects*
D000067531:Alarmins; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D037502:Galectin 3; D016209:Interleukin-8
COPD; DAMP; airway inflammation; ll-37; mitochondrial damps