Baclofen, a GABABR Agonist, Ameliorates Immune-Complex Mediated Acute Lung Injury by Modulating Pro-Inflammatory Mediators

PLoS One

Eleanor D. Lederer¹  Shunying Jin²  Jeffrey D. Ritzenthaler²  Kenneth R. McLeish²  Michael L. Merchant²  Jesse Roman²  Mostafa Fraig²  Madhavi J. Rane²  Jon B. Klein³  Alex B. Lentsch⁴  Michelle T. Barati⁵  Edilson Torres-Gonzalez⁵ 

[1] Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, United States of America;Department of Medicine, University of Louisville, Louisville, Kentucky, United States of America;Department of Pathology, University of Louisville, Louisville, Kentucky, United States of America;Department of Physiology, University of Louisville, Louisville, Kentucky, United States of America;Robley Rex VA Medical Center, Zorn Avenue, Louisville, Kentucky, United States of America

关键词: Neutrophils;    Pulmonary imaging;    Apoptosis;    Pneumocytes;    Immunoblotting;    Inflammation;    Immunoblot analysis;    MAPK signaling cascades;   

DOI  :  10.1371/journal.pone.0121637

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC) deposition-induced acute lung injury (ALI). Components of gamma amino butyric acid (GABA) signaling, including GABA B receptor 2 (GABABR2), GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI. We hypothesized that baclofen would regulate IC-induced ALI by preserving pulmonary GABABR expression. Rats were subjected to sham injury or IC-induced ALI and two hours later rats were treated intratracheally with saline or 1 mg/kg baclofen for 2 additional hours and sacrificed. ALI was assessed by vascular leakage, histology, TUNEL, and lung caspase-3 cleavage. ALI increased total protein, tumor necrosis factor α (TNF-α and interleukin-1 receptor associated protein (IL-1R AcP), in the bronchoalveolar lavage fluid (BALF). Moreover, ALI decreased lung GABABR2 expression, increased phospho-p38 MAPK, promoted IκB degradation and increased neutrophil influx in the lung. Administration of baclofen, after initiation of ALI, restored GABABR expression, which was inhibited in the presence of a GABABR antagonist, CGP52432. Baclofen administration activated pulmonary phospho-ERK and inhibited p38 MAPK phosphorylation and IκB degradation. Additionally, baclofen significantly inhibited pro-inflammatory TNF-α and IL-1βAcP release and promoted BAL neutrophil apoptosis. Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling. Interestingly, GABABR2 expression was regulated in the type II pneumocytes in lung tissue sections from lung injured patients, further suggesting a physiological role for GABABR2 in the repair process of lung damage. GABABR2 agonists may play a potential therapeutic role in ALI.

【 授权许可】

CC BY