To further explore the impact of HHIP haploinsufficiency on the development of COPD, metabolomic profiling using an untargeted liquid chromatography-tandem mass spectroscopy (LC-MS/MS) platform was performed on the plasma, urine, and lung tissue from Hhip+/− heterozygote and Hhip+/+ wild type mice exposed to either room air or 6 months of cigarette smoke (2 × 2 experimental design). This evidence concerns the gene HHIP and chronic obstructive pulmonary disease.