Browsing by Author "Yang, Xiaofeng"

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Open Access
A novel injury site-natural antibody targeted complement inhibitor protects against lung transplant injury.
(American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2021-06) Li, Changhai; Patel, Kunal; Tu, Zhenxiao; Yang, Xiaofeng; Kulik, Liudmila; Alawieh, Ali; Allen, Patterson; Cheng, Qi; Wallace, Caroline; Kilkenny, Jane; Kwon, Jennie; Gibney, Barry; Cantu, Edward; Sharma, Ashish; Pipkin, Mauricio; Machuca, Tiago; Emtiazjoo, Amir; Goddard, Martin; Holers, V Michael; Nadig, Satish; Christie, Jason; Tomlinson, Stephen; Atkinson, Carl
Complement is known to play a role in ischemia and reperfusion injury (IRI). A general paradigm is that complement is activated by self-reactive natural IgM antibodies (nAbs), after they engage postischemic neoepitopes. However, a role for nAbs in lung transplantation (LTx) has not been explored. Using mouse models of LTx, we investigated the role of two postischemic neoepitopes, modified annexin IV (B4) and a subset of phospholipids (C2), in LTx. Antibody deficient Rag1-/- recipient mice were protected from LTx IRI. Reconstitution with either B4 or C2nAb restored IRI, with C2 significantly more effective than B4 nAb. Based on these information, we developed/characterized a novel complement inhibitor composed of single-chain antibody (scFv) derived from the C2 nAb linked to Crry (C2scFv-Crry), a murine inhibitor of C3 activation. Using an allogeneic LTx, in which recipients contain a full nAb repertoire, C2scFv-Crry targeted to the LTx, inhibited IRI, and delayed acute rejection. Finally, we demonstrate the expression of the C2 neoepitope in human donor lungs, highlighting the translational potential of this approach.
Open Access
MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis
(Frontiers in Immunology) Zhong, Chao; Min, Kisuk; Zhao, Zhiqiang; Zhang, Cheng; Gao, Erhe; Huang, Yan; Zhang, Xinbo; Baldini, Margaret; Roy, Rajika; Yang, Xiaofeng; Koch, Walter J; Bennett, Anton M; Yu, Jun
Cardiac fibrosis, a pathological condition due to excessive extracellular matrix (ECM) deposition in the myocardium, is associated with nearly all forms of heart disease. The processes and mechanisms that regulate cardiac fibrosis are not fully understood. In response to cardiac injury, macrophages undergo marked phenotypic and functional changes and act as crucial regulators of myocardial fibrotic remodeling. Here we show that the mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) in macrophages is involved in pressure overload-induced cardiac fibrosis. Cardiac pressure overload resulting from transverse aortic constriction (TAC) leads to the upregulation of Mkp-5 gene expression in the heart. In mice lacking MKP-5, p38 MAPK and JNK were hyperactivated in the heart, and TAC-induced cardiac hypertrophy and myocardial fibrosis were attenuated. MKP-5 deficiency upregulated the expression of the ECM-degrading matrix metalloproteinase-9 (Mmp-9) in the Ly6Clow (M2-type) cardiac macrophage subset. Consistent with in vivo findings, MKP-5 deficiency promoted MMP-9 expression and activity of pro-fibrotic macrophages in response to IL-4 stimulation. Furthermore, using pharmacological inhibitors against p38 MAPK, JNK, and ERK, we demonstrated that MKP-5 suppresses MMP-9 expression through a combined effect of p38 MAPK/JNK/ERK, which subsequently contributes to the inhibition of ECM-degrading activity. Taken together, our study indicates that pressure overload induces MKP-5 expression and facilitates cardiac hypertrophy and fibrosis. MKP-5 deficiency attenuates cardiac fibrosis through MAPK-mediated regulation of MMP-9 expression in Ly6Clow cardiac macrophages.