RT Journal Article
T1 Mice inflammatory responses to inhaled aerosolized LPS: effects of various forms of human alpha1-antitrypsin
A1 Pérez Luz, Sara
A1 Sivaraman, Kokilavani
A1 Wrenger, Sabine
A1 Liu, Bin
A1 Schaudien, Dirk
A1 Hesse, Christina
A1 Gomez-Mariano, Gema
A1 Sewald, Katherina
A1 DeLuca, David
A1 Wurm, María J.
A1 Pino, Paco
A1 Welte, Tobias
A1 Martinez-Delgado, Beatriz
A1 Janciauskiene, Sabina
AB 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.
PB Oxford University Press
YR 2022
FD 2022-08-31
LK https://hdl.handle.net/20.500.14352/102049
UL https://hdl.handle.net/20.500.14352/102049
LA eng
NO Authorship: K.Si.: sample analysis (immunohistochemistry, ELISA, real-time PCR); S.W.: data presentation and manuscript preparation; B.L. and D.L.: data analysis and data presentation; D.S.: histopathology, immunohistochemistry, digitalization, and image analysis; C.H. and K.Se.: mouse model, sample collection, and sample analysis; M.J.W. and P.P.: concept and preparation of recAAT; G.G.M., S.P.L., and B.M.D.: RNA-seq; T.W.: concept; S.J.: concept and manuscript preparation; all authors added comments to the manuscript and read the final version.
DS Docta Complutense
RD 8 abr 2025