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.

Keywords: asthmatic airway remodeling; hedgehog signaling; lung development; repairment in tissue and immune system; targets pathogen.

Figure 1

Asymmetric hedgehog activation model that maintains distinct compartmental identity. We propose that differential Hh activation is a promising mechanism for maintaining compartmental-specific identity as well as function in the lungs. Endogenous inhibitors of Hh activation may be lost, disrupting the physiological asymmetry of Hh and resulting in altered compartmental identity and structural changes found in lung disorders.

Figure 2

Airway remodeling. Allergens or environmental exposure damage the airway epithelium, which leads to activation of immune cells through releasing soluble factors. Airway epithelial and inflammatory cells contribute to the production of autocrine and paracrine factors that induce the proliferation, expansion, and activation of airway smooth cells, which ultimately initiate the morphogenesis in the lung development. Consequently, they produce a suitable environment for sustaining the chronic inflammation that causes the airway remodeling.

Figure 3

Sonic hedgehog signaling pathway(A) In the absence of the Shh ligand, Patched-1 (Ptch1) inhibits the Smoothened receptor (SMO), and SMO cannot enter the primary cilium. The phosphorylation of GLIS can be phosphorylated by the complex of glycogen synthase kinase 3b (GSK3b), protein kinase A (PKA), and casein kinase 1 (CK1). The phosphorylated GLI-2R and GLI-3R were formed into two possible destinations: proteasome degradation and nucleus translocation to suppress the transcription of target genes. (B) Hedgehog proteins bind to Ptch1 on the cell surface level, and SMO enters to primary cilium to activate GLI through Suppressor of fused (SUFU) detachment. Then, GLI-2R (mostly) andGLI-3R translocate to the nucleus.

Figure 4

Canonical and non-canonical pathway. (A) In the canonical pathway, a ligand, Ptch1 or SMO activation, and transcription factors are involved. (B) In the non-canonical Hh ligand-independent pathway, in which Ptch1 interacts with cyclin B1 and recruits this first form of an apoptotic complex to its C-terminal domain that consists of adaptor protein Dral, the CARD-containing protein Tucan-1, and caspase-9. Caspase-9 activation is followed by caspase-3 activation, which results in apoptosis. (C) In the ligand-dependent non-canonical signaling pathway, the linkage of Ptch1 with cyclin B1 and the proapoptotic complex is disrupted by Hh binding, most likely due to a conformational shift in Ptch1, resulting in enhanced proliferation and survival. Red-highlighted and grey-shaded caspase shapes indicate active and inactive caspases, respectively.

Figure 5

Schematic drawing of overall hypothesis and the mechanism by which Sonic Hedgehog mediates airway remodeling. In the Er or Ga, the Hh or Skn attach to the HhN. The Shh ligand attaches with Ptch through CDO and is ultimately activated the SMO and COS, SUFU, GLI-1/GLI-2 complex through β-arrestin or KIF-3A. Meanwhile, this complex activates the GLI-1/2 and translocates to the nucleus, where it activates and promotes the airway remodeling through three aberrant Hh signaling expressions—ECM synthesis and deposition, ASMC and fibroblast proliferation, and airway tissue fibrosis—which increase Th2 differentiation and inflammation and EMT synthesis. However, the exact role of Shh in airway remodeling via EMT is not yet clear (noted as???). Abbreviations: HhN, Hedgehog N-terminal domain; Skn, skinny hedgehog; COS, Kinesin-like protein costa; SUFU, suppressor of fused; KIF-3A, Kinesin family member-3A; CDO, CAM-related/downregulated by oncogenes; Smo, smooth receptor; ptch, patch receptor; Er and Ga, endoplasmic reticulum and Golgi apparatus; Hh, hedgehog; Shh, Sonic Hedgehog; Ihh, Indian Hedgehog; Dhh, Desert Hedgehog; EMT, epithelial–mesenchymal transition; IL-4, Interleukin-4; Th-2, T helper-2.

Figure 6

A proposed mechanism for what occurs during pathogenic and immune system interaction with the Hh signaling pathway. Pathogens become a cause to damage the host tissue and encourage the activation of the Hh signaling pathway. Pathogens play an essential role in immunity and the repair process due to key roles in. If Hh signaling is not regulated properly, it can cause fibrosis, immune cell imbalances, or T-cell receptors (TCR) selection. Pathogens such as Epstein–Barr Virus (EBV), Hepatitis B and C virus (HBV and HCV), Human Immunodeficiency Viruses (HIV), and Helicobacter Pylori (H.P.) have been shown to directly alter Hh pathway activity. Once Hh signaling is activated, it can aggravate or restrain these damaging outcomes.