Increased Expression of LASI lncRNA Regulates the Cigarette Smoke and COPD Associated Airway Inflammation and Mucous Cell Hyperplasia Marko Manevski 1 , Dinesh Devadoss 1 , Christopher Long 1 , Shashi P. Singh 2 , Mohd Wasim Nasser 3 , Glen M. Borchert 4 , Madhavan N. Nair 1 , Irfan Rahman 5 , Mohan Sopori 2 and Hitendra S. Chand 1 * 1 Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States, 2 Respiratory Immunology Program, Lovelace Respiratory Research Institute, Albuquerque, NM, United States, 3 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States, 4 Department of Pharmacology, University of South Alabama, Mobile, AL, United States, 5 Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, United States Research Impact: Cigarette smoke (CS) exposure is strongly associated with chronic obstructive pulmonary disease (COPD). In respiratory airways, CS exposure disrupts airway barrier functions, mucous/phlegm production, and basic immune responses of airway epithelial cells. Based on our recent identification of a specific immunomodulatory long noncoding RNA (lncRNA), we investigated its role in CS-induced responses in bronchial airways of cynomolgus macaque model of CS-induced COPD and in former smokers with and without COPD. The lncRNA was significantly upregulated in CS- induced macaque airways and in COPD airways that exhibited higher mucus expression and goblet cell hyperplasia. Experimental models of cells derived from COPD subjects recapitulated the augmented inflammation and mucus expression following the smoke challenge. Blocking of 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. Rationale: In conducting airways, CS disrupts airway epithelial functions, mucociliary clearances, and innate immune responses that are primarily orchestrated by human bronchial epithelial cells (HBECs). Mucus hypersecretion and dysregulated immune response are the hallmarks of chronic bronchitis (CB) that is often exacerbated by CS. Notably, we recently identified a long noncoding RNA (lncRNA) antisense to ICAM-1 (LASI) that mediates airway epithelial responses. Objective: To investigate the role of LASI lncRNA in CS-induced airway inflammation and mucin hyperexpression in an animal model of COPD, and in HBECs and lung tissues from Frontiers in Immunology | www.frontiersin.org June 2022 | Volume 13 | Article 803362 1 Edited by: Wendy W. J. Unger, Erasmus MC-Sophia Children’s Hospital, Netherlands Reviewed by: Venkataramana Sidhaye, Johns Hopkins University, United States Dhyan Chandra, University at Buffalo, United States *Correspondence: Hitendra S. Chand hchand@fiu.edu Specialty section: This article was submitted to Mucosal Immunity, a section of the journal Frontiers in Immunology Received: 27 October 2021 Accepted: 09 May 2022 Published: 14 June 2022 Citation: Manevski M, Devadoss D, Long C, Singh SP, Nasser MW, Borchert GM, Nair MN, Rahman I, Sopori M and Chand HS (2022) Increased Expression of LASI lncRNA Regulates the Cigarette Smoke and COPD Associated Airway Inflammation and Mucous Cell Hyperplasia. Front. Immunol. 13:803362. doi: 10.3389/fimmu.2022.803362 ORIGINAL RESEARCH published: 14 June 2022 doi: 10.3389/fimmu.2022.803362