The synergistic link between sonic hedgehog signaling pathway and gut-lung axis: Its influential role toward chronic obstructive pulmonary disease progression.

Sonic Hedgehog (SHH) is an evolutionarily conserved signaling pathway essential for embryonic development, tissue homeostasis, and tumorigenesis. Aberrant activation of the SHH pathway induces various types of cancer and different types of immune dysregulation. SHH is an extremely important morphogen during lung development, as it regulates the interaction between epithelial and mesenchymal transitions (EMT) in the airways. Cigarette smoking triggers the EMT and activates the SHH signaling pathway, which leads to lung damage and the development of various lung diseases, such as COPD, a smoker's disease. SHH also directs the gut-lung axis (GLA) formation via epithelial-mesenchymal signaling. The abruption or alteration of GLA formation is also responsible for COPD pathogenesis. In this review, we elucidate an overview of the SHH pathway and its inhibitor HHIP, SHH's prominence during lung development, and the dysregulation of the SHH signaling pathway in COPD pathogenesis and its link with COPD clinical features. We also provide insights into the SHH pathway linked with the nicotine pathway and gut-lung axis and their influence on COPD pathogenesis.