Slide Presentations: Monday, October 24, 2011 |

The Role of TLR4 and HMGB1 in the Ischemia/Reperfusion-Mediated Mitochondrial Dysfunction FREE TO VIEW

Awungjia Leke Tambo, MD; Elizabeth Jacobs, MD; Meetha Medhora, PhD; Stephanie Gruenloh, BS; Ying Gao, BS; Irshad Ali, PhD
Chest. 2011;140(4_MeetingAbstracts):914A. doi:10.1378/chest.1119709
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PURPOSE: We investigated potential links between IIS activation and MD in a rat model of unilateral “warm” ischemia and reperfusion (IR) of the lung. Specifically, we aimed to determine whether IR induced MD and increments in TLR4 and HMGB1.

METHODS: Sprague Dawley rats were subjected to surgically-induced unilateral left lung ischemia for 60 minutes followed by reperfusion for two hours in vivo. Injury was assessed histologically by H&E and myeloperoxidase identified immunohistochemically. Western blot identified HMGB1 and TLR4 proteins and Caspase 3 activity was measured using a fluorimetric pseudosubstrate. Cultured pulmonary artery endothelial cells (PAEC) loaded with JC1, a mitochondrial membrane potential (MMP) dye, were used to determine the effect of HMGB1 on MMP.

RESULTS: IR injury evoked atelectasis, hemorrhage and influx of polymorphonuclear cells. Increased caspase 3 activity, TLR4 and HMGB1 protein expression were observed in IR left lung relative to right lung. Complex I activity was decreased by roughly a factor of 2 in IR lungs over that of right lungs from the same hosts. HMGB1 reduces PAECs MMP within 60 minutes.

CONCLUSIONS: IR-stimulates increased expression of HMGB1 and TLR4, and is associated with altered mitochondrial complex I activity. Because HMGB1 causes mitochondrial membrane depolarization in isolated PAECs, we speculate that signaling by HMGB1 through TLR4 receptors may directly link IR-evoked activation of the IIS to apoptosis.

CLINICAL IMPLICATIONS: Such studies are valuable in determining the mechanisms for the development of lung injury and in the future may be instrumental in developing strategies for controlling IR-induced inflammation and lung injury leading to expedited recovery

DISCLOSURE: The following authors have nothing to disclose: Awungjia Leke Tambo, Elizabeth Jacobs, Meetha Medhora, Stephanie Gruenloh, Ying Gao, Irshad Ali

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