Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury

Background Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. Methods Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. Results The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney. Conclusion The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

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The Relative Roles Of Volutrauma And Atelectrauma In A Mouse Model Of Ventilator-induced Lung Injury

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a2157 ◽

2010 ◽

Author(s):

Adrian S. Seah ◽

Kara A. Grant ◽

Gilman B. Allen ◽

Minara Aliyeva ◽

Jason H.T. Bates

Keyword(s):

Lung Injury ◽

Mouse Model ◽

Ventilator Induced Lung Injury

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Inhaled Anesthetics Exert Different Protective Properties in a Mouse Model of Ventilator-Induced Lung Injury

Anesthesia & Analgesia ◽

10.1213/ane.0000000000001296 ◽

2016 ◽

Vol 123 (1) ◽

pp. 143-151 ◽

Cited By ~ 20

Author(s):

Karl Michael Strosing ◽

Simone Faller ◽

Veronica Gyllenram ◽

Helen Engelstaedter ◽

Hartmut Buerkle ◽

...

Keyword(s):

Lung Injury ◽

Mouse Model ◽

Protective Properties ◽

Inhaled Anesthetics ◽

Ventilator Induced Lung Injury

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Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00073.2011 ◽

2011 ◽

Vol 301 (2) ◽

pp. L161-L170 ◽

Cited By ~ 12

Author(s):

Otgonchimeg Rentsendorj ◽

Mahendra Damarla ◽

Neil R. Aggarwal ◽

Ji-Young Choi ◽

Laura Johnston ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Mouse Model ◽

Time Course ◽

Fold Increase ◽

Ventilator Induced Lung Injury ◽

Volume Ventilation ◽

Mrna And Protein Expression ◽

Oxide Synthase ◽

Synergistic Increase

Phosphodiesterase 2A (PDE2A) is stimulated by cGMP to hydrolyze cAMP, a potent endothelial barrier-protective molecule. We previously found that lung PDE2A contributed to a mouse model of ventilator-induced lung injury (VILI). The purpose of the present study was to determine the contribution of PDE2A in a two-hit mouse model of 1-day intratracheal (IT) LPS followed by 4 h of 20 ml/kg tidal volume ventilation. Compared with IT water controls, LPS alone (3.75 μg/g body wt) increased lung PDE2A mRNA and protein expression by 6 h with a persistent increase in protein through day 4 before decreasing to control levels on days 6 and 10. Similar to the PDE2A time course, the peak in bronchoalveolar lavage (BAL) neutrophils, lactate dehydrogenase (LDH), and protein concentration also occurred on day 4 post-LPS. IT LPS (1 day) and VILI caused a threefold increase in lung PDE2A and inducible nitric oxide synthase (iNOS) and a 24-fold increase in BAL neutrophilia. Compared with a control adenovirus, PDE2A knockdown with an adenovirus expressing a short hairpin RNA administered IT 3 days before LPS/VILI effectively decreased lung PDE2A expression and significantly attenuated BAL neutrophilia, LDH, protein, and chemokine levels. PDE2A knockdown also reduced lung iNOS expression by 53%, increased lung cAMP by nearly twofold, and improved survival from 47 to 100%. We conclude that in a mouse model of LPS/VILI, a synergistic increase in lung PDE2A expression increased lung iNOS and alveolar inflammation and contributed significantly to the ensuing acute lung injury.

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