Related Experiment Video

Updated: May 28, 2026

An Epithelial Abrasion Model for Studying Corneal Wound Healing
04:45

An Epithelial Abrasion Model for Studying Corneal Wound Healing

Published on: December 29, 2021

HHIP's dynamic role in epithelial wound healing reveals a potential mechanism of COPD susceptibility

Dávid Deritei1, Wardatul Jannat Anamika1, Anny Xiaobo Zhou1,2

  • 1Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.

Proceedings of the National Academy of Sciences of the United States of America
|May 26, 2026
PubMed

Insights

Dysfunctional Hedgehog interacting protein (HHIP) impairs epithelial wound healing, potentially causing emphysema in chronic obstructive pulmonary disease (COPD). This HHIP dysfunction disrupts normal cell repair processes, contributing to COPD development.

Area of Science:

  • Pulmonary Medicine
  • Systems Biology
  • Genetics

Background:

  • Genetic variants near Hedgehog interacting protein (HHIP) are linked to increased chronic obstructive pulmonary disease (COPD) risk.
  • The precise role of HHIP in COPD pathogenesis is not fully understood.
  • HHIP is a known negative regulator of the Hedgehog signaling pathway.

Purpose of the Study:

  • To elucidate the mechanism by which HHIP dysfunction contributes to COPD pathogenesis, specifically emphysema.
  • To investigate HHIP's role in epithelial wound healing processes relevant to COPD.
  • To utilize a systems biology approach to model HHIP's function in the context of COPD.

Main Methods:

  • Development and analysis of two Boolean models to simulate HHIP function and Hedgehog pathway regulation.
  • Validation of Boolean models using experimental evidence from scientific literature.
  • Analysis of single-cell and single-nucleus RNA-Seq data from COPD patient cohorts and Hhip heterozygous knockout mice.

Main Results:

  • Dysfunctional HHIP leads to a loss of negative feedback on GLI transcription factors.
  • This disruption triggers a complete epithelial-mesenchymal transition (EMT), hindering proper wound closure.
  • Supporting evidence found in COPD patient data and Hhip knockout mouse models indicates aberrant wound healing.

Conclusions:

  • Aberrant epithelial wound healing due to HHIP dysfunction is a potential primary driver of COPD-associated emphysema.
  • Chronic epithelial damage, exacerbated by cigarette smoke, combined with HHIP dysfunction, may lead to emphysema.
  • This study proposes a novel mechanism linking HHIP genetics to COPD pathogenesis through impaired wound repair.

Keywords:
BooleanCOPDHHIPmechanismnetworks

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