Metabolomic profiling in a Hedgehog Interacting Protein (Hhip) murine model of chronic obstructive pulmonary disease View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-05-31

AUTHORS

Emily S. Wan, Yan Li, Taotao Lao, Weiliang Qiu, Zhiqiang Jiang, John D. Mancini, Caroline A. Owen, Clary Clish, Dawn L. DeMeo, Edwin K. Silverman, Xiaobo Zhou

ABSTRACT

Genetic variants annotated to the hedgehog interacting protein (HHIP) are robustly associated with chronic obstructive pulmonary disease (COPD). Hhip haploinsufficiency in mice leads to increased susceptibility towards the development of emphysema following exposure to chronic cigarette smoke (CS). To explore the molecular pathways which contribute to increased susceptibility, we performed metabolomic profiling using high performance liquid chromatography tandem mass spectroscopy (LC/MS-MS) on plasma, urine, and lung tissue of Hhip+/− heterozygotes and wild type (Hhip+/+) C57/BL6 mice exposed to either room-air or CS for six months. Univariate comparisons between groups were made with a combined fold change ≥2 and Student’s t-test p-value < 0.05 to denote significance; associations with mean alveolar chord length (MACL), a quantitative measure of emphysema, and gene-by-environment interactions were examined using empiric Bayes-mediated linear models. Decreased urinary excretion of cotinine despite comparable plasma levels was observed in Hhip+/− heterozygotes; a strong gene-by-smoking association was also observed. Correlations between MACL and markers of oxidative stress such as urinary methionine sulfoxide were observed in Hhip+/− but not in Hhip+/+ mice. Metabolite set enrichment analyses suggest reduced antioxidant capacity and alterations in macronutrient metabolism contribute to increased susceptibility to chronic CS-induced oxidative stress in Hhip haploinsufficiency states. More... »

PAGES

2504

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-02701-4

DOI

http://dx.doi.org/10.1038/s41598-017-02701-4

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1085634131

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28566717


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28 schema:description Genetic variants annotated to the hedgehog interacting protein (HHIP) are robustly associated with chronic obstructive pulmonary disease (COPD). Hhip haploinsufficiency in mice leads to increased susceptibility towards the development of emphysema following exposure to chronic cigarette smoke (CS). To explore the molecular pathways which contribute to increased susceptibility, we performed metabolomic profiling using high performance liquid chromatography tandem mass spectroscopy (LC/MS-MS) on plasma, urine, and lung tissue of Hhip+/− heterozygotes and wild type (Hhip+/+) C57/BL6 mice exposed to either room-air or CS for six months. Univariate comparisons between groups were made with a combined fold change ≥2 and Student’s t-test p-value < 0.05 to denote significance; associations with mean alveolar chord length (MACL), a quantitative measure of emphysema, and gene-by-environment interactions were examined using empiric Bayes-mediated linear models. Decreased urinary excretion of cotinine despite comparable plasma levels was observed in Hhip+/− heterozygotes; a strong gene-by-smoking association was also observed. Correlations between MACL and markers of oxidative stress such as urinary methionine sulfoxide were observed in Hhip+/− but not in Hhip+/+ mice. Metabolite set enrichment analyses suggest reduced antioxidant capacity and alterations in macronutrient metabolism contribute to increased susceptibility to chronic CS-induced oxidative stress in Hhip haploinsufficiency states.
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34 schema:keywords BL6 mice
35 Bayes
36 C57/BL6 mice
37 MACl
38 Student's t-test p-value
39 alterations
40 alveolar chord length
41 analysis
42 antioxidant capacity
43 association
44 capacity
45 changes
46 chord length
47 chronic cigarette smoke
48 chronic obstructive pulmonary disease
49 cigarette smoke
50 comparable plasma levels
51 comparison
52 correlation
53 cotinine
54 development
55 development of emphysema
56 disease
57 emphysema
58 enrichment analysis
59 environment interaction
60 excretion
61 exposure
62 fold change
63 genes
64 genetic variants
65 group
66 haploinsufficiency
67 haploinsufficiency state
68 hedgehog interacting protein
69 heterozygotes
70 high-performance liquid chromatography-tandem mass spectroscopy
71 interacting protein
72 interaction
73 length
74 levels
75 linear model
76 liquid chromatography-tandem mass spectroscopy
77 lung tissue
78 macronutrient metabolism
79 markers
80 mass spectroscopy
81 measures
82 metabolism
83 metabolites
84 metabolomic profiling
85 methionine sulfoxide
86 mice
87 model
88 molecular pathways
89 months
90 murine model
91 obstructive pulmonary disease
92 oxidative stress
93 p-value
94 pathway
95 performance liquid chromatography-tandem mass spectroscopy
96 plasma
97 plasma levels
98 profiling
99 protein
100 pulmonary disease
101 quantitative measures
102 significance
103 smoke
104 smoking association
105 spectroscopy
106 state
107 stress
108 strong gene
109 sulfoxide
110 susceptibility
111 t-test p-value
112 tandem mass spectroscopy
113 tissue
114 univariate comparisons
115 urinary excretion
116 urine
117 variants
118 wild-type C57/BL6 mice
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