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p38 Mitogen-activated protein kinase inhibition reduces inflammatory cytokines in a brain-dead transplant donor animal model.
Heart Lung Circ 2009; 18(6):393-400HL

Abstract

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 TNFalpha 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 TNFalpha 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 TNFalpha 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.

Authors+Show Affiliations

Department of Cardiothoracic Surgery, Alfred Hospital, Monash University, Melbourne, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19647484

Citation

Oto, Takahiro, et al. "P38 Mitogen-activated Protein Kinase Inhibition Reduces Inflammatory Cytokines in a Brain-dead Transplant Donor Animal Model." Heart, Lung & Circulation, vol. 18, no. 6, 2009, pp. 393-400.
Oto T, Calderone A, Li Z, et al. P38 Mitogen-activated protein kinase inhibition reduces inflammatory cytokines in a brain-dead transplant donor animal model. Heart Lung Circ. 2009;18(6):393-400.
Oto, T., Calderone, A., Li, Z., Rosenfeldt, F. L., & Pepe, S. (2009). P38 Mitogen-activated protein kinase inhibition reduces inflammatory cytokines in a brain-dead transplant donor animal model. Heart, Lung & Circulation, 18(6), pp. 393-400. doi:10.1016/j.hlc.2009.05.706.
Oto T, et al. P38 Mitogen-activated Protein Kinase Inhibition Reduces Inflammatory Cytokines in a Brain-dead Transplant Donor Animal Model. Heart Lung Circ. 2009;18(6):393-400. PubMed PMID: 19647484.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - p38 Mitogen-activated protein kinase inhibition reduces inflammatory cytokines in a brain-dead transplant donor animal model. AU - Oto,Takahiro, AU - Calderone,Alicia, AU - Li,Zhihe, AU - Rosenfeldt,Franklin L, AU - Pepe,Salvatore, Y1 - 2009/07/31/ PY - 2008/02/05/received PY - 2009/03/19/revised PY - 2009/05/12/accepted PY - 2009/8/4/entrez PY - 2009/8/4/pubmed PY - 2010/3/3/medline SP - 393 EP - 400 JF - Heart, lung & circulation JO - Heart Lung Circ VL - 18 IS - 6 N2 - UNLABELLED: 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 TNFalpha 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 TNFalpha 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 TNFalpha 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. SN - 1444-2892 UR - https://www.unboundmedicine.com/medline/citation/19647484/p38_Mitogen_activated_protein_kinase_inhibition_reduces_inflammatory_cytokines_in_a_brain_dead_transplant_donor_animal_model_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1443-9506(09)00946-9 DB - PRIME DP - Unbound Medicine ER -