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Lung Transcriptomics during Protective Ventilatory Support in Sepsis-Induced Acute Lung Injury.

Acosta-Herrera M, Lorenzo-Diaz F, Pino-Yanes M, Corrales A, Valladares F, Klassert TE, Valladares B, Slevogt H, Ma SF, Villar J, Flores C - PLoS ONE (2015)

Bottom Line: However, it is currently unknown how they exert the protective effects.Unexpectedly, the 'neuron projection morphogenesis' process was one of the most significantly deregulated in LVT.Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated.

View Article: PubMed Central - PubMed

Affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Research Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain; Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain.

ABSTRACT
Acute lung injury (ALI) is a severe inflammatory process of the lung. The only proven life-saving support is mechanical ventilation (MV) using low tidal volumes (LVT) plus moderate to high levels of positive end-expiratory pressure (PEEP). However, it is currently unknown how they exert the protective effects. To identify the molecular mechanisms modulated by protective MV, this study reports transcriptomic analyses based on microarray and microRNA sequencing in lung tissues from a clinically relevant animal model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley rats. At 24 hours post-CLP, septic animals were randomized to three ventilatory strategies: spontaneous breathing, LVT (6 ml/kg) plus 10 cmH2O PEEP and high tidal volume (HVT, 20 ml/kg) plus 2 cmH2O PEEP. Healthy, non-septic, non-ventilated animals served as controls. After 4 hours of ventilation, lung samples were obtained for histological examination and gene expression analysis using microarray and microRNA sequencing. Validations were assessed using parallel analyses on existing publicly available genome-wide association study findings and transcriptomic human data. The catalogue of deregulated processes differed among experimental groups. The 'response to microorganisms' was the most prominent biological process in septic, non-ventilated and in HVT animals. Unexpectedly, the 'neuron projection morphogenesis' process was one of the most significantly deregulated in LVT. Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated. Additional analyses revealed 'VEGF signaling' as a central underlying response mechanism to all the septic groups (spontaneously breathing or mechanically ventilated). Based on this data, we conclude that a co-deregulation of 'VEGF signaling' along with 'neuron projection morphogenesis', which have been never anticipated in ALI pathogenesis, promotes lung-protective effects of LVT with high levels of PEEP.

No MeSH data available.


Related in: MedlinePlus

Biological processes associated with significantly deregulated genes compared to the non-septic controls in each experimental group (x-axis).The enrichment score (left y-axis), a log transformation of the geometric mean of all the enrichment p-value, indicates the processes that play major roles in each group. The right y-axis reflects a transformation of the FDR to globally correct the enrichment p-value for the pathways included within each biological process. Whiskers represent their lower and upper FDR values. The horizontal discontinuous line represents the transformed value for a FDR = 0.05.
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pone.0132296.g006: Biological processes associated with significantly deregulated genes compared to the non-septic controls in each experimental group (x-axis).The enrichment score (left y-axis), a log transformation of the geometric mean of all the enrichment p-value, indicates the processes that play major roles in each group. The right y-axis reflects a transformation of the FDR to globally correct the enrichment p-value for the pathways included within each biological process. Whiskers represent their lower and upper FDR values. The horizontal discontinuous line represents the transformed value for a FDR = 0.05.

Mentions: Using the list of deregulated genes per group, we then assessed their contribution on biological processes, as this could be more informative to reveal the mechanisms that are being activated or repressed during ALI than focusing on particular genes. As expected, several biological processes were found deregulated with an extensive overlap among the three groups. However, the levels of deregulation per group were different in most cases (Fig 6). Given that the experimental model involved systemic inflammation, we anticipated that the ‘response to microorganisms’ would be one of the main deregulated processes among the septic groups. However, although it was detected as the leading process in SHVT and SS (FDR<1x10-3 in both comparisons), it was not significantly enriched in SLVT (FDR = 0.245). These results reflect again the additive effects of mechanical and systemic damage in the SHVT. Noteworthy, a few unanticipated processes such as the ‘neuron projection morphogenesis’ and the ‘antioxidant activity’ were evidenced in the SLVT group (FDR = 0.002 and FDR = 0.05, respectively).


Lung Transcriptomics during Protective Ventilatory Support in Sepsis-Induced Acute Lung Injury.

Acosta-Herrera M, Lorenzo-Diaz F, Pino-Yanes M, Corrales A, Valladares F, Klassert TE, Valladares B, Slevogt H, Ma SF, Villar J, Flores C - PLoS ONE (2015)

Biological processes associated with significantly deregulated genes compared to the non-septic controls in each experimental group (x-axis).The enrichment score (left y-axis), a log transformation of the geometric mean of all the enrichment p-value, indicates the processes that play major roles in each group. The right y-axis reflects a transformation of the FDR to globally correct the enrichment p-value for the pathways included within each biological process. Whiskers represent their lower and upper FDR values. The horizontal discontinuous line represents the transformed value for a FDR = 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492998&req=5

pone.0132296.g006: Biological processes associated with significantly deregulated genes compared to the non-septic controls in each experimental group (x-axis).The enrichment score (left y-axis), a log transformation of the geometric mean of all the enrichment p-value, indicates the processes that play major roles in each group. The right y-axis reflects a transformation of the FDR to globally correct the enrichment p-value for the pathways included within each biological process. Whiskers represent their lower and upper FDR values. The horizontal discontinuous line represents the transformed value for a FDR = 0.05.
Mentions: Using the list of deregulated genes per group, we then assessed their contribution on biological processes, as this could be more informative to reveal the mechanisms that are being activated or repressed during ALI than focusing on particular genes. As expected, several biological processes were found deregulated with an extensive overlap among the three groups. However, the levels of deregulation per group were different in most cases (Fig 6). Given that the experimental model involved systemic inflammation, we anticipated that the ‘response to microorganisms’ would be one of the main deregulated processes among the septic groups. However, although it was detected as the leading process in SHVT and SS (FDR<1x10-3 in both comparisons), it was not significantly enriched in SLVT (FDR = 0.245). These results reflect again the additive effects of mechanical and systemic damage in the SHVT. Noteworthy, a few unanticipated processes such as the ‘neuron projection morphogenesis’ and the ‘antioxidant activity’ were evidenced in the SLVT group (FDR = 0.002 and FDR = 0.05, respectively).

Bottom Line: However, it is currently unknown how they exert the protective effects.Unexpectedly, the 'neuron projection morphogenesis' process was one of the most significantly deregulated in LVT.Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated.

View Article: PubMed Central - PubMed

Affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Research Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain; Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain.

ABSTRACT
Acute lung injury (ALI) is a severe inflammatory process of the lung. The only proven life-saving support is mechanical ventilation (MV) using low tidal volumes (LVT) plus moderate to high levels of positive end-expiratory pressure (PEEP). However, it is currently unknown how they exert the protective effects. To identify the molecular mechanisms modulated by protective MV, this study reports transcriptomic analyses based on microarray and microRNA sequencing in lung tissues from a clinically relevant animal model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley rats. At 24 hours post-CLP, septic animals were randomized to three ventilatory strategies: spontaneous breathing, LVT (6 ml/kg) plus 10 cmH2O PEEP and high tidal volume (HVT, 20 ml/kg) plus 2 cmH2O PEEP. Healthy, non-septic, non-ventilated animals served as controls. After 4 hours of ventilation, lung samples were obtained for histological examination and gene expression analysis using microarray and microRNA sequencing. Validations were assessed using parallel analyses on existing publicly available genome-wide association study findings and transcriptomic human data. The catalogue of deregulated processes differed among experimental groups. The 'response to microorganisms' was the most prominent biological process in septic, non-ventilated and in HVT animals. Unexpectedly, the 'neuron projection morphogenesis' process was one of the most significantly deregulated in LVT. Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated. Additional analyses revealed 'VEGF signaling' as a central underlying response mechanism to all the septic groups (spontaneously breathing or mechanically ventilated). Based on this data, we conclude that a co-deregulation of 'VEGF signaling' along with 'neuron projection morphogenesis', which have been never anticipated in ALI pathogenesis, promotes lung-protective effects of LVT with high levels of PEEP.

No MeSH data available.


Related in: MedlinePlus