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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

Baclofen inhibits pulmonary TNF-α expression in lung injured animals.(A) Lung tissue homogenates from control, LI and LI+B treated animals were immunoblotted with anti-TNF-α and anti-GADH antisera. GAPDH was used as an internal control. Four animals per group were used. (B) Densitometric units of TNF-α for all 4 animals/per group were normalized to their corresponding GAPDH densitometric units. The data was averaged, analyzed and quantitated.
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pone.0121637.g002: Baclofen inhibits pulmonary TNF-α expression in lung injured animals.(A) Lung tissue homogenates from control, LI and LI+B treated animals were immunoblotted with anti-TNF-α and anti-GADH antisera. GAPDH was used as an internal control. Four animals per group were used. (B) Densitometric units of TNF-α for all 4 animals/per group were normalized to their corresponding GAPDH densitometric units. The data was averaged, analyzed and quantitated.

Mentions: While we have not identified the cellular target of baclofen, we examined changes in pro-inflammatory mediator TNF-α in the control lung tissue and in the injured lung tissue before and after baclofen treatment. Fig 2A and 2B demonstrates that compared to the control lung tissue, TNF-α expression was markedly increased in the lung tissue after ALI and this was significantly blocked by baclofen administration suggesting a global baclofen effect on the injured lung tissue and confirming the therapeutic potential of baclofen in ALI. Four animals were used in each of the three groups tested.


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)

Baclofen inhibits pulmonary TNF-α expression in lung injured animals.(A) Lung tissue homogenates from control, LI and LI+B treated animals were immunoblotted with anti-TNF-α and anti-GADH antisera. GAPDH was used as an internal control. Four animals per group were used. (B) Densitometric units of TNF-α for all 4 animals/per group were normalized to their corresponding GAPDH densitometric units. The data was averaged, analyzed and quantitated.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121637.g002: Baclofen inhibits pulmonary TNF-α expression in lung injured animals.(A) Lung tissue homogenates from control, LI and LI+B treated animals were immunoblotted with anti-TNF-α and anti-GADH antisera. GAPDH was used as an internal control. Four animals per group were used. (B) Densitometric units of TNF-α for all 4 animals/per group were normalized to their corresponding GAPDH densitometric units. The data was averaged, analyzed and quantitated.
Mentions: While we have not identified the cellular target of baclofen, we examined changes in pro-inflammatory mediator TNF-α in the control lung tissue and in the injured lung tissue before and after baclofen treatment. Fig 2A and 2B demonstrates that compared to the control lung tissue, TNF-α expression was markedly increased in the lung tissue after ALI and this was significantly blocked by baclofen administration suggesting a global baclofen effect on the injured lung tissue and confirming the therapeutic potential of baclofen in ALI. Four animals were used in each of the three groups tested.

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