Hhip haploinsufficiency sensitizes mice to age-related emphysema

Significance Genome-wide association studies (GWAS) have been very successful in discovering genetic loci associated with complex traits. However, only few studies applied murine models to investigate how GWAS genes contribute to human lung diseases. Motivated by GWAS linking Hedgehog interacting protein (HHIP) to emphysema and impairments in lung function, this study demonstrated that Hhip+/− mice developed spontaneous emphysema and lung function impairment over time. Moreover, emphysema, associated with increased oxidative stress in Hhip+/− lungs, was prevented by treating the mice with the antioxidant, N-acetyl cysteine (NAC). This post-GWAS functional study connects aging-related diseases, molecular mechanisms, and potential therapy in a genetic haploinsufficient murine model, which may lead to improvements in understanding pathophysiologic concepts of alveolar loss related to aging. 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.