Role of Novel Immunoregulatory Long Noncoding RNAs in Airway Epithelial Pathophysiology and Chronic Pulmonary Disease

Authors

Marko ManevskiFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biomedical Sciences

First Advisor's Name

Hitendra S Chand

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Alexander Agoulnik

Second Advisor's Committee Title

Committee Member

Third Advisor's Name

Madhavan P Nair

Third Advisor's Committee Title

Committee Member

Fourth Advisor's Name

Irfan Rahman

Fourth Advisor's Committee Title

Committee Member

Fifth Advisor's Name

Hoshang J Unwalla

Fifth Advisor's Committee Title

Committee Member

Keywords

COPD, long noncoding RNA, lncRNA, airway epithelium, inflammation

Date of Defense

6-28-2022

Abstract

COPD is currently the third leading cause of death globally, accounting for approximately 6% of all deaths in 2019, and cigarette smoke (CS) is the primary risk factor for disease development.

Transcriptomic analysis of a 3D in vitro model using differentiated human airway epithelial cells (AECs) identified a novel lncRNA on the antisense strand of ICAM-1 or LASI that showed increased expression upon CS exposure. The lncRNA was significantly upregulated in CS-induced Rhesus macaque airways and in human COPD airways that exhibited higher mucus expression and goblet cell hyperplasia, which was recapitulated in vitro. Blocking lncRNA expression in cell culture setting suppressed the smoke-induced and COPD-associated dysregulated mucoinflammatory response suggesting that this airway specific immunomodulatory lncRNA may represent a novel target to mitigate the smoke-mediated inflammation and mucus hyperexpression.

Additionally, not much is known about contribution of airway lncRNAs in COVID-19. RNA-sequencing analysis of nasal samples from COVID-19 patients showed significantly higher expression of secretory mucin and inflammatory gene signatures compared to the uninfected controls. COVID-19 patients showed elevated expression of inflammatory factors, airway mucins and associated transcription factors. LASI was induced in COVID-19 patients with high viral-load. A SARS-CoV-2 infected 3D-airway model largely recapitulated these clinical findings. Molecular dynamic modeling further suggested a stable interaction between viral RNA and LASI lncRNA. Notably, blocking LASI lncRNA reduced SARS-CoV-2 viral load and suppressed MUC5AC mucin levels. LASI lncRNA represents an essential facilitator of SARS-CoV-2 infection and associated airway mucoinflammatory response.

Altogether, LASI lncRNA may represent a novel target to control the smoke-mediated dysregulation in airway responses and COPD exacerbations, as well as in viral infection-related inflammatory responses.

Identifier

FIDC010797

ORCID

0000-0002-7125-4468

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Recommended Citation

Manevski, Marko, "Role of Novel Immunoregulatory Long Noncoding RNAs in Airway Epithelial Pathophysiology and Chronic Pulmonary Disease" (2022). FIU Electronic Theses and Dissertations. 5006.
https://digitalcommons.fiu.edu/etd/5006