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PMID: 27444019 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Hhip haploinsufficiency sensitizes mice to age-related emphysema.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 113 ·No. 32 ·2016-00-09 ·Pages E4681-7

Lao T, Jiang Z, Yun J, Qiu W, Guo F, Huang C, Mancini JD, Gupta K, Laucho-Contreras ME, Naing ZZ, Zhang L, Perrella MA, Owen CA, Silverman EK, Zhou X

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.

Keywords
COPD HHIP aging emphysema oxidative stress
MeSH Terms
Acetylcysteine/pharmacology Age Factors Animals Carrier Proteins/genetics Emphysema/etiology Glutathione/metabolism Glutathione S-Transferase pi/physiology Haploinsufficiency Lung/pathology,physiology Lung Compliance Membrane Glycoproteins/genetics Mice Mice, Inbred C57BL Oxidative Stress
Chemicals
Carrier Proteins Hhip protein, mouse Membrane Glycoproteins Glutathione S-Transferase pi Gstp1 protein, mouse Glutathione Acetylcysteine
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Lao Taotao
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Jiang Zhiqiang
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Yun Jeong
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;
Qiu Weiliang
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Guo Feng
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Huang Chunfang
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Mancini John Dominic
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Gupta Kushagra
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Laucho-Contreras Maria E
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;
Naing Zun Zar Chi
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Zhang Li
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Perrella Mark A
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.
Owen Caroline A
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;
Silverman Edwin K
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;
Zhou Xiaobo
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; [email protected].
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1602342113
Email
[email protected]
Published
2016-00-09
Epub
2016-00-21
Pages
E4681-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC4987811
Subset
IM
Grants
NHLBI NIH HHS · R01 HL075478 · United States
NHLBI NIH HHS · R33 HL120794 · United States
NHLBI NIH HHS · P01 HL105339 · United States
NIAID NIH HHS · R01 AI111475 · United States
NHLBI NIH HHS · R21 HL111835 · United States
NHLBI NIH HHS · R01 HL127200 · United States
NHLBI NIH HHS · P01 HL114501 · United States
NHLBI NIH HHS · R01 HL111759 · United States
External Links
PubMed source DOI: 10.1073/pnas.1602342113 PMC Full Text View journal details
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