Περίληψη:
Chronic obstructive pulmonary disease (COPD) is linked to both cigarette
smoking and genetic determinants. We have previously identified
iron-responsive element binding protein 2 (IRP2) as an important COPD
susceptibility gene and have shown that IRP2 protein is increased in the
lungs of individuals with COPD. Here we demonstrate that mice deficient
in Irp2 were protected from cigarette smoke (CS)-induced experimental
COPD. By integrating RNA immunoprecipitation followed by sequencing
(RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional
enrichment clustering analysis, we identified Irp2 as a regulator of
mitochondrial function in the lungs of mice. Irp2 increased
mitochondrial iron loading and levels of cytochrome c oxidase (COX),
which led to mitochondrial dysfunction and subsequent experimental COPD.
Frataxin-deficient mice, which had higher mitochondria! iron loading,
showed impaired airway mucociliary clearance (MCC) and higher pulmonary
inflammation at baseline, whereas mice deficient in the synthesis of
cytochrome c oxidase, which have reduced COX, were protected from
CS-induced pulmonary inflammation and impairment of MCC. Mice treated
with a mitochondria! iron chelator or mice fed a low-iron diet were
protected from CS-induced COPD. Mitochondrial iron chelation also
alleviated CS-induced impairment of MCC, CS-induced pulmonary
inflammation and CS-associated lung injury in mice with established
COPD, suggesting a critical functional role and potential therapeutic
intervention for the mitochondrial-iron axis in COPD.
Συγγραφείς:
Cloonan, Suzanne M.
Glass, Kimberly
Laucho-Contreras, Maria E.
and Bhashyam, Abhiram R.
Cervo, Morgan
Pabon, Maria A. and
Konrad, Csaba
Polverino, Francesca
Siempos, Ilias I.
Perez,
Elizabeth
Mizumura, Kenji
Ghosh, Manik C.
Parameswaran,
Harikrishnan
Williams, Niamh C.
Rooney, Kristen T.
Chen,
Zhi-Hua
Goldklang, Monica P.
Yuan, Guo-Cheng
Moore, Stephen
C.
Demeo, Dawn L.
Rouault, Tracey A.
D'Armiento, Jeanine M.
and Schon, Eric A.
Manfredi, Giovanni
Quackenbush, John and
Mahmood, Ashfaq
Silverman, Edwin K.
Owen, Caroline A.
Choi,
Augustine M. K.
