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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

Microscopy images stained with hematoxylin-eosin showing representative lung histopathological features under different strategies of MV: a) non-ventilated non-septic controls (NA); b) Septic, anesthetized, spontaneous breathing after 4 hours (SS); c) septic after 4 hours of MV at LVT + 10 cm H2O PEEP (SLVT); and d) septic after 4 hours of MV at HVT + 2 cm H2O PEEP (SHVT).
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pone.0132296.g001: Microscopy images stained with hematoxylin-eosin showing representative lung histopathological features under different strategies of MV: a) non-ventilated non-septic controls (NA); b) Septic, anesthetized, spontaneous breathing after 4 hours (SS); c) septic after 4 hours of MV at LVT + 10 cm H2O PEEP (SLVT); and d) septic after 4 hours of MV at HVT + 2 cm H2O PEEP (SHVT).

Mentions: The degree of lung injury differed among septic animals, including atelectasis, pulmonary edema, and acute inflammatory infiltrates. In ventilated animals, gas exchange was impaired, showing a ratio of partial pressure arterial oxygen and fraction of inspired oxygen (PaO2/FiO2) <250 mmHg at the end of 4 hours of MV, indicative of ALI. The SLVT group had less lung injury than the SS animals, suggestive of the additive effects of mechanical and systemic damage. The SHVT animals had the most severe injury in terms of pulmonary infiltrates, atelectasis and hemorrhage (Fig 1). These results overlap extensively with those from previous studies reported by our group using this experimental model [14,16], and evidence the protective mechanical effect of LVT on severely injured lungs.


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)

Microscopy images stained with hematoxylin-eosin showing representative lung histopathological features under different strategies of MV: a) non-ventilated non-septic controls (NA); b) Septic, anesthetized, spontaneous breathing after 4 hours (SS); c) septic after 4 hours of MV at LVT + 10 cm H2O PEEP (SLVT); and d) septic after 4 hours of MV at HVT + 2 cm H2O PEEP (SHVT).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132296.g001: Microscopy images stained with hematoxylin-eosin showing representative lung histopathological features under different strategies of MV: a) non-ventilated non-septic controls (NA); b) Septic, anesthetized, spontaneous breathing after 4 hours (SS); c) septic after 4 hours of MV at LVT + 10 cm H2O PEEP (SLVT); and d) septic after 4 hours of MV at HVT + 2 cm H2O PEEP (SHVT).
Mentions: The degree of lung injury differed among septic animals, including atelectasis, pulmonary edema, and acute inflammatory infiltrates. In ventilated animals, gas exchange was impaired, showing a ratio of partial pressure arterial oxygen and fraction of inspired oxygen (PaO2/FiO2) <250 mmHg at the end of 4 hours of MV, indicative of ALI. The SLVT group had less lung injury than the SS animals, suggestive of the additive effects of mechanical and systemic damage. The SHVT animals had the most severe injury in terms of pulmonary infiltrates, atelectasis and hemorrhage (Fig 1). These results overlap extensively with those from previous studies reported by our group using this experimental model [14,16], and evidence the protective mechanical effect of LVT on severely injured lungs.

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