Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp New thiazolidinedione LPSF/GQ-2 inhibits NFκB and MAPK activation in LPS-induced acute lung inflammation Laise Aline Martins dos Santos a,b , Gabriel Barros Rodrigues c , Fernanda Virgínia Barreto Mota c , Maria Eduarda Rocha de França c , Karla Patrícia de Souza Barbosa e , Wilma Helena de Oliveira c , Sura Wanessa Santos Rocha f , Deniele Bezerra Lós d , Amanda Karolina Soares Silva c , Teresinha Gonçalves da Silva c , Christina Alves Peixoto a,g, ⁎ a Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, PE, Brazil b Postgraduate Program in Biosciences and Biotechnology for Health (PPGBBS), Oswaldo Cruz Foundation (FIOCRUZ-PE)/Aggeu Magalhães Institute (IAM), Recife, PE, Brazil c Postgraduate Program in Federal University of Pernambuco, Recife, PE, Brazil d Postgraduate Program in Biotechnology/RENORBIO, Federal University of Pernambuco, Recife, PE, Brazil e Federal University of Pernambuco, Recife, PE, Brazil f State University of Pernambuco, Recife, PE, Brazil g Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Brazil ARTICLE INFO Keywords: Acute lung injury Thiazolidinediones (TDZs) NFκB MAPKs ABSTRACT Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are responsible for high mortality rates in critical patients. Despite > 50 years of intensive research, there is no pharmacologically effective treatment to treat ALI. PPARs agonists, chemically named thiazolidinediones (TZDs) have emerged as potential drugs for the treatment of ALI and ARDS due to their anti-inflammatory efficacy. The present study aims to evaluate the potential anti-inflammatory effects of new TZDs derivatives, LPSF/GQ-2 and LPSF/RA-4, on ALI induced by LPS. BALB/c mice were divided into five groups: 1) Control; 2) LPS intranasal 25 μg; 3) LPSF/GQ-2 30 mg/kg + LPS; 4) LPSF/RA-4 20 mg/kg + LPS; and 5) DEXA 1 mg/Kg + LPS. BALF analyses revealed that LPSF/GQ-2 and LPSF/RA-4 reduced NO levels in BALF and inflammatory cell infiltration induced by LPS. MPO levels were also reduced by the LPSF/GQ-2 and LPSF/RA-4 pre-treatments. In contrast, histopathological analyses showed better tissue protection with LPSF/GQ-2 than DEXA and LPSF/RA-4 groups. Similarly, LPSF/GQ-2 reduced in- flammatory markers (IL-1, iNOS, TNFα, IL-1β, IL-6) better than LPSF/RA-4. The LPSF/GQ-2 anti-inflammatory action could be attributed to the inhibition of NFκB, ERK, p38, and PARP pathways. In contrast, LPSF/RA-4 had no effect on the expression of p38, JNK, NFκB. The present study indicates that LPSF/GQ-2 presents a potential therapeutic role as an anti-inflammatory drug for ALI. 1. Introduction Acute lung injury (ALI) and its severe form, acute respiratory dis- tress syndrome (ARDS), are considered important causes of death in critical patients. Epidemiological studies estimate that ALI/ARDS is associated with hospital mortality ranging from 30 to 60% [1–3]. The first description of ALI/ARDS was made in 1967 by ASHBAUGH and collaborators [4]. In general, ALI/ARDS is defined by acute-onset tachypnea, hypoxemia, diffuse pulmonary infiltrates, and loss of lung compliance, and characterized by high short-term mortality in adults. The heterogeneous nature of ALI/ARDS and the presence of additional risk factors makes difficult to assess its molecular basis [5]. Lipopolysaccharide (LPS) is an important agent used to induce ALI/ ARDS in animals models due to its relation with sepsis [6,7]. LPS is a principal component of the outer membrane of Gram-negative bacteria, and an important inductor agent to elicit inflammatory responses, shock, and death [6]. In monocytes, the activation of Toll-Like Re- ceptors (TLR4) by LPS, activates transcription factors like NFκB and AP- 1[8]. The NFκB pathway regulates the expression of several inflammatory mediators such as cytokines, chemokines, adhesion molecules, COX-2 and iNOS [9]. The excessive activation of NFκB is associated with the https://doi.org/10.1016/j.intimp.2018.02.011 Received 11 September 2017; Received in revised form 26 January 2018; Accepted 14 February 2018 ⁎ Corresponding author at: Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Avenida Professor Moraes Rego, s/n, Cidade Universitária, Recife, PE, Postal Code: 50.670- 420, Brazil. E-mail address: cpeixoto@cpqam.fiocruz.br (C.A. Peixoto). International Immunopharmacology 57 (2018) 91–101 1567-5769/ © 2018 Published by Elsevier B.V. T