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Baclofen, a GABABR agonist, ameliorates immune-complex mediated acute lung injury by modulating pro-inflammatory mediators.

Jin S, Merchant ML, Ritzenthaler JD, McLeish KR, Lederer ED, Torres-Gonzalez E, Fraig M, Barati MT, Lentsch AB, Roman J, Klein JB, Rane MJ - PLoS ONE (2015)

Bottom Line: 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).Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling.GABABR2 agonists may play a potential therapeutic role in ALI.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

GABABR2 expression is regulated in type II pneumocytes of lung tissue sections of lung injured patients compared to the controls.This is a representative image (40X) of anti-GABABR2 immunohistochemistry that was performed on lung tissue sections from control and lung injured patient (lung injured patients n = 4). (A) Anti-GABABR2 was detected in the bronchial epithelium of the control lungs and (B) in the type I and type II pneumocytes of control lung. (C) Increased type II pneumocytes were detected in the lungs of the lung injured patients. Moreover, GABABR2 expression was mainly detected in the type II pneumocytes in these patients suggesting a physiological role for GABABR2 in the repair to lung damage. (D) zoomed image of 6C.
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pone.0121637.g006: GABABR2 expression is regulated in type II pneumocytes of lung tissue sections of lung injured patients compared to the controls.This is a representative image (40X) of anti-GABABR2 immunohistochemistry that was performed on lung tissue sections from control and lung injured patient (lung injured patients n = 4). (A) Anti-GABABR2 was detected in the bronchial epithelium of the control lungs and (B) in the type I and type II pneumocytes of control lung. (C) Increased type II pneumocytes were detected in the lungs of the lung injured patients. Moreover, GABABR2 expression was mainly detected in the type II pneumocytes in these patients suggesting a physiological role for GABABR2 in the repair to lung damage. (D) zoomed image of 6C.

Mentions: We obtained human lung tissue sections from control and lung injured patients. These human lung tissue sections were subjected to anti-GABABR2 immunohistochemistry. In Fig 6 (panel A and B) we see that in the control lung GABABR2 expression is detected mainly in the bronchial epithelium and in type I and II pneumocytes. In contrast, in injured lung (Fig 6C and 6D), we see increased type II pneumocytes compared to the control lung section and GABABR2 staining was mainly detected in type II pneumocytes suggesting a physiological role for GABABR2 in the repair and reaction to some insults to the lung parenchyma. Considering the bronchial epithelium as an internal positive control (3+). The level of GABABR2 staining in type II pneumocytes of ALI patients is 2+ and in healthy control is 0–1+.


Baclofen, a GABABR agonist, ameliorates immune-complex mediated acute lung injury by modulating pro-inflammatory mediators.

Jin S, Merchant ML, Ritzenthaler JD, McLeish KR, Lederer ED, Torres-Gonzalez E, Fraig M, Barati MT, Lentsch AB, Roman J, Klein JB, Rane MJ - PLoS ONE (2015)

GABABR2 expression is regulated in type II pneumocytes of lung tissue sections of lung injured patients compared to the controls.This is a representative image (40X) of anti-GABABR2 immunohistochemistry that was performed on lung tissue sections from control and lung injured patient (lung injured patients n = 4). (A) Anti-GABABR2 was detected in the bronchial epithelium of the control lungs and (B) in the type I and type II pneumocytes of control lung. (C) Increased type II pneumocytes were detected in the lungs of the lung injured patients. Moreover, GABABR2 expression was mainly detected in the type II pneumocytes in these patients suggesting a physiological role for GABABR2 in the repair to lung damage. (D) zoomed image of 6C.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4388838&req=5

pone.0121637.g006: GABABR2 expression is regulated in type II pneumocytes of lung tissue sections of lung injured patients compared to the controls.This is a representative image (40X) of anti-GABABR2 immunohistochemistry that was performed on lung tissue sections from control and lung injured patient (lung injured patients n = 4). (A) Anti-GABABR2 was detected in the bronchial epithelium of the control lungs and (B) in the type I and type II pneumocytes of control lung. (C) Increased type II pneumocytes were detected in the lungs of the lung injured patients. Moreover, GABABR2 expression was mainly detected in the type II pneumocytes in these patients suggesting a physiological role for GABABR2 in the repair to lung damage. (D) zoomed image of 6C.
Mentions: We obtained human lung tissue sections from control and lung injured patients. These human lung tissue sections were subjected to anti-GABABR2 immunohistochemistry. In Fig 6 (panel A and B) we see that in the control lung GABABR2 expression is detected mainly in the bronchial epithelium and in type I and II pneumocytes. In contrast, in injured lung (Fig 6C and 6D), we see increased type II pneumocytes compared to the control lung section and GABABR2 staining was mainly detected in type II pneumocytes suggesting a physiological role for GABABR2 in the repair and reaction to some insults to the lung parenchyma. Considering the bronchial epithelium as an internal positive control (3+). The level of GABABR2 staining in type II pneumocytes of ALI patients is 2+ and in healthy control is 0–1+.

Bottom Line: 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).Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling.GABABR2 agonists may play a potential therapeutic role in ALI.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus