Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Recombinant Human HAPLN1 Mitigates Pulmonary Emphysema by Increasing TGF-β Receptor I and Sirtuins Levels in Human Alveolar Epithelial Cells

  • Yongwei Piao (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • So Yoon Yun (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Zhicheng Fu (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Ji Min Jang (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Moon Jung Back (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Ha Hyung Kim (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Dae Kyong Kim (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University)
  • Received : 2023.06.08
  • Accepted : 2023.06.24
  • Published : 2023.09.30
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Abstract

Chronic obstructive pulmonary disease (COPD) will be the third leading cause of death worldwide by 2030. One of its components, emphysema, has been defined as a lung disease that irreversibly damages the lungs' alveoli. Treatment is currently unavailable for emphysema symptoms and complete cure of the disease. Hyaluronan (HA) and proteoglycan link protein 1 (HAPLN1), an HA-binding protein linking HA in the extracellular matrix to stabilize the proteoglycan structure, forms a bulky hydrogel-like aggregate. Studies on the biological role of the full-length HAPLN1, a simple structure-stabilizing protein, are limited. Here, we demonstrated for the first time that treating human alveolar epithelial type 2 cells with recombinant human HAPLN1 (rhHAPLN1) increased TGF-β receptor 1 (TGF-β RI) protein levels, but not TGF-β RII, in a CD44-dependent manner with concurrent enhancement of the phosphorylated Smad3 (p-Smad3), but not p-Smad2, upon TGF-β1 stimulation. Furthermore, rhHAPLN1 significantly increased sirtuins levels (i.e., SIRT1/2/6) without TGF-β1 and inhibited acetylated p300 levels that were increased by TGF-β1. rhHAPLN1 is crucial in regulating cellular senescence, including p53, p21, and p16, and inflammation markers such as p-NF-κB and Nrf2. Both senile emphysema mouse model induced via intraperitoneal rhHAPLN1 injections and porcine pancreatic elastase (PPE)-induced COPD mouse model generated via rhHAPLN1-containing aerosols inhalations showed a significantly potent efficacy in reducing alveolar spaces enlargement. Preclinical trials are underway to investigate the effects of inhaled rhHAPLN1-containing aerosols on several COPD animal models.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea grant (NRF-2017M3A9D8048414) funded by the Korean Government (Ministry of Science and ICT). We thank Dr. Eui Man Jeong (College of Pharmacy, Jeju National University, Republic of Korea) for discussion and interpretation on reactive oxygen species.

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