Chronic obstructive pulmonary disease (COPD) is characterized by intense lung infiltrations of immune cells (macrophages and monocytes). Lipopolysaccharide (LPS) activates macrophages/monocytes, leading to production of tumor necrosis factor α (TNFα) and other cytokines, which cause subsequent lung damages. In the current study, our results demonstrated that AS-703026, a novel MEK/ERK inhibitor, suppressed LPS-induced TNFα mRNA expression and protein secretion in RAW 264.7 murine macrophages, and in murine bone marrow-derived macrophages (BMDMs). Meanwhile, TNFα production in LPS-stimulated COPD patents’ peripheral blood mononuclear cells (PBMCs) was also repressed by AS-703026. At the molecular level, we showed that AS-703026 blocked LPS-induced MEK/ERK activation in above macrophages/monocytes. However, restoring ERK activation in AS-703026-treated RAW 264.7 cells by introducing a constitutive-actively (CA)-ERK1 only partially reinstated LPS-mediated TNFα production. Meanwhile, AS-703026 could still inhibit TNFα response in ERK1/2-depleted (by shRNA) RAW 264.7 cells. Significantly, we found that AS-703026 inhibited LPS-induced nuclear factor κB (NFκB) activation in above macrophages and COPD patients’ PBMCs. In vivo, oral administration of AS-703026 inhibited LPS-induced TNFα production and endotoxin shock in BALB/c mice. Together, we show that AS-703026 in vitro inhibits LPS-induced TNFα production in macrophages/monocytes, and in vivo protects mice from LPS-induced endotoxin shock. Thus, it could be further studied as a useful anti-inflammatory therapy for COPD patients.

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Transboundary water cooperation (TWC) is an important theme of international cooperation. We conducted macro-level research on TWC from the perspective of inter-country relations and constructed a theoretical framework in which multidimensional proximity influences the formation of global TWC. We explained how multidimensional proximity and the constituent elements comprehensively influence the cooperative willingness and ability of actors, which directly drive the generation of global TWC. During the empirical research phase, we constructed the TWC frequency and intensity networks based on historical TWC events data from 1992 to 2013. By using social network analysis and QAP regression analysis, the spatial structure and proximity effect of water cooperation linkages are examined. It can be found that: (1) the reconstruction of territorial space on the eve of the end of the Cold War led to the peak of water cooperation events in 1992. The overall scale of events in the Post-Cold War era was relatively high and fluctuated steadily. (2) Water cooperation linkages have distinct spatial heterogeneity and are concentrated in the Eurasian and the African continents. Water cooperation is sensitive to geographical distance, and high-intensity water cooperation linkages exist in only a few areas. (3) China, Egypt, Germany, the United States, and Russia have prominent positions in the network. The United States, Japan, and other extra-regional powers actively participated in TWC in the Eastern Hemisphere. (4) The regression results show that geographical, economic, organizational, and colonial proximity significantly affect the intensity of water cooperation among countries.