Abstract
COPD affects millions of people and is now ranked as the third leading cause of death worldwide. This largely untreatable chronic airway disease results in irreversible destruction of lung architecture. The small lung hypothesis is now supported by epidemiological, physiological and clinical studies. Accordingly, the early and severe COPD phenotype carries the most dreadful prognosis and finds its roots during lung growth. Pathophysiological mechanisms remain poorly understood and implicate individual susceptibility (genetics), a large part of environmental factors (viral infections, tobacco consumption, air pollution) and the combined effects of those triggers on gene expression. Genetic susceptibility is most likely involved as the disease is severe and starts early in life. The latter observation led to the identification of Mendelian inheritance via disease-causing variants of SERPINA1 - known as the basis for alpha-1 anti-trypsin deficiency, and TERT. In the last two decades multiple genome wide association studies (GWAS) identified many single nucleotide polymorphisms (SNPs) associated with COPD. High significance SNPs are located in 4q31 near HHIP which encodes an evolutionarily highly conserved physiological inhibitor of the Hedgehog signaling pathway (HH). HHIP is critical to several in utero developmental lung processes. It is also implicated in homeostasis, injury response, epithelial-mesenchymal transition and tumor resistance to apoptosis. A few studies have reported decreased HHIP RNA and protein levels in human adult COPD lungs. HHIP+/- murine models led to emphysema. HH pathway inhibitors, such as vismodegib and sonidegib, are already validated in oncology, whereas other drugs have evidenced in vitro effects. Targeting the Hedgehog pathway could lead to a new therapeutic avenue in COPD. In this review, we focused on the early and severe COPD phenotype and the small lung hypothesis by exploring genetic susceptibility traits that are potentially treatable, thus summarizing promising therapeutics for the future.