Purpose: Deterioration of the native lung from lung injury occurs in the majority of patients following single lung transplant, but its pathogenesis remains unknown. Here, we demonstrate that pulmonary intravascular CX₃CR1^highLy6C^low monocytes (Ly6C^lowM) in the donor lungs migrate to the native lung and lead to infiltration of neutrophils, the key mediators of lung injury.

Methods: Allogeneic single lung transplant was performed utilizing wild-type, CX₃CR1^gfp/+, and CX₃CR1 knockout (KO) mice. Donor lungs were flushed using standard preservatives. Intravenous clodronate liposomes (IV Clo-lip) were used to deplete intravascular monocytes. Lung myeloid populations, including neutrophils and Ly6C^lowM, were identified by flow cytometry. Data are presented as mean ± SEM. Student's t-test was used to compare means. Experimental groups consisted of n=2-8.

Results: Donor lungs revealed 2-5% of myeloid cells to be intravascular Ly6C^lowM. At 24 hours following allogeneic single lung transplant, native lungs demonstrated a 3-fold increase in neutrophils compared to sham thoracotomy (1.6±0.2×10⁶ v. 0.5±0.1×10⁶, p=0.02). Using CD45.1 donors and CD45.2 recipients, 8% of the Ly6C^lowM in the native lung were of donor origin. IV Clo-lip depleted Ly6C^lowM in donor lungs (<0.5%). Allogeneic recipients of Ly6C^lowM-depleted donor lungs demonstrated no donor-derived Ly6C^lowM in the native lung and markedly decreased neutrophilia (0.8±0.1×10⁶ vs. 1.6±0.2×10⁶, p<0.01). Similarly, CX₃CR1 KO donor lungs showed decreased Ly6C^lowM and recipients of CX₃CR1 KO lungs revealed suppressed native lung neutrophilia compared to recipients of CX₃CR1^gfp/+ lungs that have preserved Ly6C^lowM (1.1±0.2 v. 1.8±0.1×10⁶, p=0.04).

Conclusion: Donor-derived pulmonary intravascular Ly6C^lowM migrate to the native lung following single lung transplant and induce neutrophilia. Depletion of these monocytes in the donor lung protects the native lung from neutrophilia.

CITATION INFORMATION: Chiu S, Zheng Z, Sun H, DeCamp, Jr M, Budinger G, Perlman H, Misharin A, Bharat A. Donor-Derived Monocytes Migrate to the Contralateral Lung and Cause Neutrophilia Following Single Lung Transplant. Am J Transplant. 2016;16 (suppl 3).

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