title: Hhip haploinsufficiency sensitizes mice to age-related emphysema.
abstract: Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 s (FEV1), in general population samples by genome-wide association studies. However, in vivo evidence connecting Hhip to age-related FEV1 decline and emphysema development is lacking. Herein, using Hhip heterozygous mice (Hhip(+/-)), we observed increased lung compliance and spontaneous emphysema in Hhip(+/-) mice starting at 10 mo of age. This increase was preceded by increases in oxidative stress levels in the lungs of Hhip(+/-) vs. Hhip(+/+) mice. To our knowledge, these results provide the first line of evidence that HHIP is involved in maintaining normal lung function and alveolar structures. Interestingly, antioxidant N-acetyl cysteine treatment in mice starting at age of 5 mo improved lung function and prevented emphysema development in Hhip(+/-) mice, suggesting that N-acetyl cysteine treatment limits the progression of age-related emphysema in Hhip(+/-) mice. Therefore, reduced lung function and age-related spontaneous emphysema development in Hhip(+/-) mice may be caused by increased oxidative stress levels in murine lungs as a result of haploinsufficiency of Hhip.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Taotao
authors.initials: T
authors.lastname: Lao
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Jeong
authors.initials: J
authors.lastname: Yun
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Chunfang
authors.initials: C
authors.lastname: Huang
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: John Dominic
authors.initials: JD
authors.lastname: Mancini
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Kushagra
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Chronic Obstructive Pulmonary Disease Program, The Lovelace Respiratory Research Institute, Albuquerque, NM 87108;
authors.forename: Maria E
authors.initials: ME
authors.lastname: Laucho-Contreras
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Zun Zar Chi
authors.initials: ZZ
authors.lastname: Naing
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Chronic Obstructive Pulmonary Disease Program, The Lovelace Respiratory Research Institute, Albuquerque, NM 87108;
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; xiaobo.zhou@channing.harvard.edu.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004646:Emphysema / Q000209:etiology*; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000502:physiology; D057895:Haploinsufficiency; D008168:Lung / Q000473:pathology / Q000502:physiology; D008170:Lung Compliance; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress
chemical_list: D002352:Carrier Proteins; C498447:Hhip protein, mouse; D008562:Membrane Glycoproteins; D051549:Glutathione S-Transferase pi; C496557:Gstp1 protein, mouse; D005978:Glutathione; D000111:Acetylcysteine
keywords: COPD; HHIP; aging; emphysema; oxidative stress