Hhip haploinsufficiency sensitizes mice to age-related emphysema

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.

AT2R deficiency mediated podocyte loss via activation of ectopic hedgehog interacting protein (Hhip) gene expression

“…Hh pathways [6,[12][13][14][15][16][17][18]. The importance of Hhip is highlighted by the findings that (i) Hhip overexpression in chondrocytes leads to severe skeletal defects [6,14]; (ii) deficient Hhip expression results in lung and pancreas malformations [6,14]; and (iii) altered Hhip gene expression is linked to several human diseases, such as pancreatitis [19], chronic obstructive pulmonary disease [18,20], and various tumors [21,22].…”

“…Hedgehog interacting protein (Hhip) was discovered as a putative antagonist of three Hh ligands, including Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh) . Acting as a structural decoy receptor, Hhip regulates cell function via either canonical or non‐canonical Hh pathways . The importance of Hhip is highlighted by the findings that (i) Hhip overexpression in chondrocytes leads to severe skeletal defects ; (ii) deficient Hhip expression results in lung and pancreas malformations ; and (iii) altered Hhip gene expression is linked to several human diseases, such as pancreatitis , chronic obstructive pulmonary disease , and various tumors .…”

Changes in the number of CD31^−CD45^−Sca-1⁺ cells and Shh signaling pathway involvement in the lungs of mice with emphysema and relevant effects of acute adenovirus infection

“…However, the underlying mechanism and whether the mechanism is linked to the canonical Shh signaling pathway remain unclear. A significant relationship between Hhip and the canonical Shh signaling pathway failed to reveal that Hhip protected against age-related emphysema in mice 42. However, the expression of Gli1 and Gli2 was increased in CS-exposed Hhip ± mice compared to that in CS-exposed Hhip +/+ mice 41.…”

“…Gene expression of Hhip in lung tissues from patients with COPD was reduced by ~32% compared to ex-smokers with normal lung function 39. More importantly, mice with Hhip haploinsufficiency ( Hhip ± ) are highly susceptible to not only more severe airspace enlargement induced by CS but also age-related emphysema compared to Hhip +/+ mice 41,42. Thus, Hhip plays a critical role in COPD pathogenesis.…”

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

“…The mechanisms which contribute to the propensity of Hhip +/− heterozygotes towards developing more severe histological and functional emphysema when exposed to chronic CS or during aging relative to their wild type counterparts are incompletely understood but are likely mediated through an increased sensitivity towards oxidative stress 6 . Given the “standardized” exposure to oxidative stress in our experiment, we hypothesize that this increased sensitivity may be due to a) reduced antioxidant capacity and b) changes in metabolism which perpetuate oxidative damage.…”