Hedgehog Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling

Abstract

The development of the embryonic lung demands complex endodermal–mesodermal interactions, which are regulated by a variety of signaling proteins. Hedgehog (Hh) signaling is vital for lung development. It plays a key regulatory role during several morphogenic mechanisms, such as cell growth, differentiation, migration, and persistence of cells. On the other hand, abnormal expression or loss of regulation of Hh signaling leads to airway asthmatic remodeling, which is characterized by cellular matrix modification in the respiratory system, goblet cell hyperplasia, deposition of collagen, epithelial cell apoptosis, proliferation, and activation of fibroblasts. Hh also targets some of the pathogens and seems to have a significant function in tissue repairment and immune-related disorders. Similarly, aberrant Hh signaling expression is critically associated with the etiology of a variety of other airway lung diseases, mainly, bronchial or tissue fibrosis, lung cancer, and pulmonary arterial hypertension, suggesting that controlled regulation of Hh signaling is crucial to retain healthy lung functioning. Moreover, shreds of evidence imply that the Hh signaling pathway links to lung organogenesis and asthmatic airway remodeling. Here, we compiled all up-to-date investigations linked with the role of Hh signaling in the development of lungs as well as the attribution of Hh signaling in impairment of lung expansion, airway remodeling, and immune response. In addition, we included all current investigational and therapeutic approaches to treat airway asthmatic remodeling and immune system pathway diseases.

Accurate and efficient estimation of local heritability using summary statistics and the linkage disequilibrium matrix

“…One plausible explanation for the pleiotropic effects of this region is that it hosts the Hedgehog (Hh)-interacting protein ( HHIP ) gene, which is associated with multiple pulmonery traits, such as FEV1/FVC ratio, chronic obstructive pulmonary disease (COPD) and lung cancer 58 – 61 . As a regulator of the Hh signaling pathway, HHIP is vital for embryonic lung development and is also involved in mature airway epithelial repair 62 . We hypothesize that the observed pleiotropic effects at this locus may be attributable to the HHIP gene and its broad influence on lung functionality 63 , 64 .…”

Different Transcriptome Features of Peripheral Blood Mononuclear Cells in Non-Emphysematous Chronic Obstructive Pulmonary Disease

“…“Hedgehog signaling pathway” was upregulated in KEGG pathway analysis in patients with non-emphysematous COPD. Hedgehog signal transduction abnormalities lead to asthmatic airway remodeling, characterized by cellular matrix modification, collagen deposition, epithelial cell proliferation, epithelial-mesenchymal transition, and fibroblast activation [ 46 ]. Hedgehog signaling also targets a function in tissue repair and immune-related disorders of asthmatic airways [ 47 ].…”

Accurate and Efficient Estimation of Local Heritability using Summary Statistics and LD Matrix

“…One plausible explanation for the pleiotropic effects of this region is that it hosts the Hedgehog (Hh)-interacting protein (HHIP) gene, which is associated with multiple pulmonery traits, such as FEV1/FVC ratio, COPD and lung cancer [54][55][56][57] . As a regulator of the Hh signalling pathway, HHIP is vital for embryonic lung development and is also involved in mature airway epithelial repair 58 . We hypothesize that the observed pleiotropic effects at this locus may be attributable to the HHIP gene and its broad influence on lung functionality 59,60 .…”