p38 Mitogen-Activated Protein Kinase Inhibition Reduces Inflammatory Cytokines in a Brain-Dead Transplant Donor Animal Model

Oto, Takahiro; Calderone, Alicia; Li, Zhihe; Rosenfeldt, Franklin L.; Pepe, Salvatore

doi:10.1016/j.hlc.2009.05.706

« Previous Next »Heart, Lung and Circulation
Volume 18, Issue 6 , Pages 393-400, December 2009

p38 Mitogen-Activated Protein Kinase Inhibition Reduces Inflammatory Cytokines in a Brain-Dead Transplant Donor Animal Model

Takahiro Oto, MD
- Department of Cardiothoracic Surgery, Alfred Hospital, and Department of Surgery, Monash University, Melbourne, Australia
Alicia Calderone, BBiomedSc(Hons)
- Department of Cardiothoracic Surgery, Alfred Hospital, and Department of Surgery, Monash University, Melbourne, Australia
Zhihe Li, MD, PhD
- Department of Pharmacology and Preclinical Research, Scios Inc., Fremont, CA, USA
Franklin L. Rosenfeldt, MD, FRACS
- Department of Cardiothoracic Surgery, Alfred Hospital, and Department of Surgery, Monash University, Melbourne, Australia
Salvatore Pepe, PhD, FAHA, FCSANZ
- Department of Cardiothoracic Surgery, Alfred Hospital, and Department of Surgery, Monash University, Melbourne, Australia
- Corresponding author at: Department of Cardiology, Royal Children's Hospital, Flemington Road, Melbourne, VIC 3052, Australia. Tel.: +61 393454114; fax: +61 3 9345 6001.

Received 5 February 2008; received in revised form 19 March 2009; accepted 12 May 2009.

The aim of this study was to determine the degree of p38 mitogen-activated protein kinase (p38 MAPK) activation in rat heart and lungs after experimentally induced brain death and to test whether SD-282, a synthetic and selective small molecule inhibitor of p38 MAPK, abrogates p38 MAPK activation invoked by this brain death model.

Methods

Adult male Sprague Dawley rats were treated with vehicle (control, n=7) or SD-282 (40mg/kg, n=6), for 15min prior to the induction of brain death and maintained with ventilatory support for 3h. IL-6 and TNFα were measured in plasma, heart and lungs using ELISA, and p38 MAPK via Western blot assay.

Results

p38 MAPK inhibition was demonstrated by lower p38 MAPK activity in lungs from SD-282-treated donors compared to control (Median [inter-quartile range]: 13.6[4.0–19.0]% vs 20.2[14.7–31.5]% activity, p=0.06). Although levels varied, significant inhibition of p38 MAPK by SD-282 was not observed in the heart. SD-282 significantly lowered IL-6 and TNFα values compared to control in plasma (64[51–81]pg/ml vs 352[200–755]pg/ml, p=0.003 and 4.3[1.5–9.0]pg/ml vs 21.1[10.5–31.5]pg/ml, p=0.015, respectively) and lungs (0.14[0.12–0.62] vs 5.8[3.6–6.0]pg/mg protein, p=0.03 and 0.41[0.33–0.45] vs 2.1[1.4–2.7]pg/mg protein, p=0.0027, respectively), however SD-282 did not significantly affect cardiac cytokine levels.

Conclusions

p38 MAPK inhibition with SD-282 decreases the pro-inflammatory response as represented by lower IL-6 and TNFα in plasma and lungs following brain death. However, although in heart this response was variable, no significant effect could be demonstrated under the present conditions.

Keywords: Brain death, Donor heart, Donor lungs, p38 Mitogen-activated protein kinase, IL-6, TNFα