Sonic Hedgehog Signaling in the Lung. From Development to Disease

Abstract

Over the past two decades, the secreted protein sonic hedgehog (SHH) has emerged as a critical morphogen during embryonic lung development, regulating the interaction between epithelial and mesenchymal cell populations in the airway and alveolar compartments. There is increasing evidence that the SHH pathway is active in adult lung diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, and lung cancer, which raises two questions: (1) What role does SHH signaling play in these diseases? and (2) Is it a primary driver of the disease or a response (perhaps beneficial) to the primary disturbance? In this review we aim to fill the gap between the well-studied period of embryonic lung development and the adult diseased lung by reviewing the hedgehog (HH) pathway during the postnatal period and in adult uninjured and injured lungs. We elucidate the similarities and differences in the epithelial-mesenchymal interplay during the fibrosis response to injury in lung compared with other organs and present a critical appraisal of tools and agents available to evaluate HH signaling.

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

“…Additionally, the exogenous expression of either Hh or VEGF has been shown to additively contribute to TGF-β-driven fibrotic disease progression in animal models (33)(34)(35)). Our results demonstrate that ITA antagonizes both Hh and VEGF signaling pathways in HSCs and that chemical inhibition of both signaling pathways together is sufficient to recapitulate ITA's inhibitory effect on MFB formation.…”

Targeting GLI factors to inhibit the Hedgehog pathway

“…When PTCH is engaged by Hh, it relieves the inhibition of SMO and the signal is transduced to the downstream transcription factors GLI1, GLI2, and GLI3, which in turn regulate the expression of Hh target genes involved in key cellular processes, such as cell cycle, survival, migration, and metabolism [2]. Given the significant involvement of Hh signaling in the development of several districts including pancreas, kidney, lung, nervous system, and limb [3][4][5], its misregulation results in multiple birth and developmental defects [6,7]. Aberrant Hh pathway activation is responsible for the tumorigenesis of several disparate human cancers including medulloblastoma (MB), rhabdomyosarcoma, melanoma, basal cell carcinoma (BCC), and breast, lung, liver, stomach, prostate, and pancreas tumors [8][9][10][11].…”

Idiopathic Pulmonary Fibrosis: Clinical Behavior, Pathogenic Mechanisms and Therapeutic Approach

“…The SHH is critical for embryonic lung formation, regulating branching morphogenesis and mesenchymal proliferation 45 . Two recent reports demonstrated the upregulation of SHH in epithelial cells lining fibrotic areas in IPF lungs while it was undetectable in normal lungs 46,47 .…”