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Right arrow Lung - transplantation

J Thorac Cardiovasc Surg 2009;137:695-702
© 2009 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

CD4+ T lymphocytes mediate acute pulmonary ischemia–reperfusion injury

Zequan Yang, MD, PhDa, Ashish K. Sharma, MBBSa, Joel Linden, PhDb, Irving L. Kron, MDa, Victor E. Laubach, PhDa,*

a Department of Surgery, University of Virginia Health System, Charlottesville, Va
b Department of Medicine, University of Virginia Health System, Charlottesville, Va

Received for publication April 17, 2008; revisions received September 18, 2008; accepted for publication October 13, 2008.

* Address for reprints: Victor E. Laubach, PhD, University of Virginia Health System, Department of Surgery, PO Box 801359, Charlottesville, VA 22908. (Email: laubach{at}virginia.edu).

Objective: Postischemic reperfusion of the lung triggers proinflammatory responses that stimulate injurious neutrophil chemotaxis. We hypothesized that T lymphocytes are recruited and activated during reperfusion and mediate subsequent neutrophil-induced lung ischemia–reperfusion injury.

Methods: An in vivo mouse model of lung ischemia–reperfusion injury was used. C57BL/6 mice were assigned to either the sham group (left thoracotomy) or 7 study groups that underwent 1-hour left hilar occlusion followed by 1 to 24 hours of reperfusion. After in vivo reperfusion, the lungs were perfused ex vivo with buffer whereby pulmonary function was assessed. Lung vascular permeability, edema, neutrophil accumulation, and cytokine/chemokine production (tumor necrosis factor {alpha}, interleukin 17, CCL3, and CXCL1) were assessed based on Evans blue dye leak, wet/dry weight ratio, myeloperoxidase level, and enzyme-linked immunosorbent assay, respectively.

Results: A preliminary study showed that 2 hours of reperfusion resulted in greater pulmonary dysfunction than 1 or 24 hours of reperfusion. The 2-hour reperfusion period was thus used for the remaining experiments. Comparable and significant protection from ischemia–reperfusion injury–induced lung dysfunction and injury occurred after antibody depletion of neutrophils or CD4+ T cells but not CD8+ T cells (P < .05 vs immunoglobulin G control). Lung ischemia–reperfusion injury was proportional to the infiltration of neutrophils but not T cells. Moreover, pulmonary neutrophil infiltration and the production of CXCL1 (KC) were significantly diminished by CD4+ T-cell depletion but not vice versa.

Conclusions: Both CD4+ T lymphocytes and neutrophils accumulate during reperfusion and contribute sequentially to lung ischemia–reperfusion injury. The data suggest that neutrophils mediate ischemia–reperfusion injury; however, CD4+ T cells play a critical role in stimulating chemokine production and neutrophil chemotaxis during ischemia–reperfusion injury.

Abbreviations and Acronyms BAL = bronchoalveolar lavage; IFN-{gamma} = interferon {gamma}; IgG = immunoglobulin G; IL = interleukin; IRI = ischemia–reperfusion injury; LC = lung compliance; mAb = monoclonal antibody; MPO = myeloperoxidase; TNF-{alpha} = tumor necrosis factor {alpha}




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