Mice inflammatory responses to inhaled aerosolized LPS: effects of various forms of human alpha1-antitrypsin. Issue 1 (10th January 2023)

• Record Type: Journal Article
• Authors: Sivaraman, Kokilavani; Wrenger, Sabine; Liu, Bin; Schaudien, Dirk; Hesse, Christina; Gomez-Mariano, Gema; Perez-Luz, Sara; Sewald, Katherina; DeLuca, David; Wurm, Maria J; Pino, Paco; Welte, Tobias; Martinez-Delgado, Beatriz; Janciauskiene, Sabina
• Is Part Of: Journal of leukocyte biology. Volume 113:Issue 1(2023)
• Page Start: 58
• Page End: 70
• Publication Date: 2023-01-10
• Subjects: endotoxin inhalation -- lung inflammation -- RNA-seq -- cytokines -- molecular forms -- oxidation -- C-terminal peptide; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1093/jleuko/qiac004
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract: Rodent models of lipopolysaccharide (LPS)–induced pulmonary inflammation are used for anti-inflammatory drug testing. We aimed to characterize mice responses to aerosolized LPS alone or with intraperitoneal (i.p.) delivery of alpha1-antitrypsin (AAT). Balb/c mice were exposed to clean air or aerosolized LPS (0.21 mg/mL) for 10 min per day, for 3 d. One hour after each challenge, animals were treated i.p. with saline or with (4 mg/kg body weight) one of the AAT preparations: native (AAT), oxidized (oxAAT), recombinant (recAAT), or peptide of AAT (C-36). Experiments were terminated 6 h after the last dose of AATs. Transcriptome data of mice lungs exposed to clean air versus LPS revealed 656 differentially expressed genes and 155 significant gene ontology terms, including neutrophil migration and toll-like receptor signaling pathways. Concordantly, mice inhaling LPS showed higher bronchoalveolar lavage fluid neutrophil counts and levels of myeloperoxidase, inducible nitric oxide synthase, IL-1β, TNFα, KC, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Plasma inflammatory markers did not increase. After i.p. application of AATs, about 1% to 2% of proteins reached the lungs but, except for GM-CSF, none of the proteins significantly influenced inflammatory markers. All AATs and C-36 significantly inhibited LPS-induced GM-CSF release. Surprisingly, only oxAAT decreased the expression of several LPS-induced inflammatory genes, such as Cxcl3, Cd14, Il1b, Nfkb1, and Nfkb2, in lung tissues. According to lung transcriptome data, oxAAT mostly affected genes related to transcriptional regulation while native AAT or recAAT affected genes of inflammatory pathways. Hence, we present a feasible mice model of local lung inflammation induced via aerosolized LPS that can be useful for systemic drug testing. Abstract : Mouse models of aerosolized LPS-induced pulmonary inflammation are useful to evaluate systemically delivered anti-inflammatory drugs like different forms of alpha1-antitrypsin.