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Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring.

ABSTRACT: The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis.We exposed Hhip haploinsufficient mice (Hhip (+/-) ) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis.We detected more severe airspace enlargement in Hhip (+/-) mice vs. wild-type littermates (Hhip (+/+) ) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip (+/-) vs. Hhip (+/+) mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip (+/-) mice compared to Hhip (+/+) mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip (+/-) mice after CS exposure.In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state.

SUBMITTER: Lao T

PROVIDER: S-EPMC4355149 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring.

Lao Taotao T Glass Kimberly K Qiu Weiliang W Polverino Francesca F Gupta Kushagra K Morrow Jarrett J Mancini John Dominic JD Vuong Linh L Perrella Mark A MA Hersh Craig P CP Owen Caroline A CA Quackenbush John J Yuan Guo-Cheng GC Silverman Edwin K EK Zhou Xiaobo X

Genome medicine 20150214 1

<h4>Background</h4>The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis.<h4>Methods</h4>We exposed Hhip haploinsufficient mice (Hhip (+/-) ) to cigarette smoke (CS) for 6 months to model the biological co ...[more]

PMID: 25763110

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Project description:RATIONALE:Matrix metalloprotease (MMP)-9 is an elastolytic endopeptidase produced by activated macrophages that may be involved in the development of human pulmonary emphysema and could be inhibited with existing compounds. Mouse models have demonstrated that excess MMP-9 production can result in permanent alveolar destruction. OBJECTIVES:To determine if MMP-9 causes cigarette smoke-induced emphysema using MMP-9 knockout mice and human samples. METHODS:Mouse lungs were analyzed for inflammation and airspace enlargement using a mainstream smoke-exposure model. Human macrophage mRNA was isolated from subjects with emphysema by laser capture microdissection. Human blood monocyte mRNA was isolated from subjects with greater than 30 pack-year smoking history. Human gene expression was determined by quantitative polymerase chain reaction and compared with emphysema severity determined by automated computed tomography analysis. Plasma Clara cell secretory protein and surfactant protein-D were quantified to measure ongoing lung injury. MEASUREMENTS AND MAIN RESULTS:Mice deficient in MMP-9 develop the same degree of cigarette smoke-induced inflammation and airspace enlargement as strain-matched controls. Macrophages are the predominant source of MMP-9 production in human emphysema specimens and similar quantities of macrophage MMP-9 mRNA is present in areas of lung with and without emphysema. Circulating monocytes produce more MMP-9 in individuals with advanced emphysema severity despite no correlation of MMP-9 with markers of ongoing lung damage. CONCLUSIONS:These results suggest that MMP-9 in humans who smoke is similar to smoke-exposed mice, where MMP-9 is present in emphysematous lung but not correlated with the emphysema. To the degree that the mechanisms of emphysema in humans who smoke resemble the mouse model, these data suggest specific inhibition of MMP-9 is unlikely to be an effective therapy for cigarette smoke-induced emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT 00757120).

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Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring.

Publications

Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring.

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