Research Paper Volume 15, Issue 7 pp 2395—2417

p21 facilitates chronic lung inflammation via epithelial and endothelial cells

Naama Levi1, *, , Nurit Papismadov1, *, , Julia Majewska1, , Lior Roitman1, , Noa Wigoda2, , Raya Eilam3, , Michael Tsoory3, , Ron Rotkopf2, , Yossi Ovadya1, , Hagay Akiva1, , Ofer Regev4, , Valery Krizhanovsky1, ,

  • 1 Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 7610001, Israel
  • 2 Department of Life Sciences Core Facilities, The Weizmann Institute of Science, Rehovot 7610001, Israel
  • 3 Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot 7610001, Israel
  • 4 Department of Immunology, The Weizmann Institute of Science, Rehovot 7610001, Israel
* Equal contribution

Received: November 8, 2022       Accepted: March 17, 2023       Published: March 30, 2023
How to Cite

Copyright: © 2023 Levi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Cellular senescence is a stable state of cell cycle arrest that regulates tissue integrity and protects the organism from tumorigenesis. However, the accumulation of senescent cells during aging contributes to age-related pathologies. One such pathology is chronic lung inflammation. p21 (CDKN1A) regulates cellular senescence via inhibition of cyclin-dependent kinases (CDKs). However, its role in chronic lung inflammation and functional impact on chronic lung disease, where senescent cells accumulate, is less understood. To elucidate the role of p21 in chronic lung inflammation, we subjected p21 knockout (p21-/-) mice to repetitive inhalations of lipopolysaccharide (LPS), an exposure that leads to chronic bronchitis and accumulation of senescent cells. p21 knockout led to a reduced presence of senescent cells, alleviated the pathological manifestations of chronic lung inflammation, and improved the fitness of the mice. The expression profiling of the lung cells revealed that resident epithelial and endothelial cells, but not immune cells, play a significant role in mediating the p21-dependent inflammatory response following chronic LPS exposure. Our results implicate p21 as a critical regulator of chronic bronchitis and a driver of chronic airway inflammation and lung destruction.


BAL: Bronchoalveolar lavage; CDK: Cyclin-dependent kinases; CDKI: Cyclin-dependent kinase inhibitor; CDKN1A: Cyclin-dependent kinase inhibitor 1A (p21); COPD: Chronic obstructive pulmonary disease; DEG: Differentially-expressed genes; GO: Gene Ontology; H&E: Hematoxylin and eosin; iBALT: Inducible bronchus-associated lymphoid tissue; LPS: Lipopolysaccharide; MMPs: Matrix Metalloproteases; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; p21-/-: p21 knockout; Rb: retinoblastoma protein; SASP: Senescence-associated secretory phenotype; SA-β-gal: Senescence-associated beta-galactosidase; WT: Wild type.