Background: Sunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets multiple receptors such as vascular endothelial growth factor receptors (VEGFRs), was approved for cancer treatment in 2006. However, it was unsuccessful in treating certain cancers, particularly metastatic breast cancer (MBC), and the mechanism underlying this “sunitinib resistance” remains unclear. Herein, we investigated whether the sunitinib-associated inferior survival benefit in MBC was due to sunitinib-induced endothelial cell (EC) injury or EC senescence. Methods: 4T1 murine breast cancer cells were used as the main breast tumor model for it produces a highly metastatic solid tumor that can spontaneously metastasize to the lung, which closely mimics highly metastatic human breast cancer. Senescence-associated β-galactosidase (SA-β-Gal, immunohistochemistry [IHC]-staining), P16, P53, and P57 (immunoblotting) were used as markers of cell senescence. A protein array containing 25 senescence-associated chemokines and the transwell chemotaxis assay were used to examine whether sunitinib increases inflammatory chemokine secretion which attracts tumor cells via chemokinesis. Flow cytometry and IHC were used to detect whether the sunitinib-induced senescent ECs recruit cancer-associated inflammatory myeloid cells. Finally, the spontaneous metastatic model was used to monitor whether sunitinib causes the formation of “pre-metastatic niche” which promotes MBC to metastasize to the lungs. Results: We demonstrated that sunitinib induced a senescence-like endothelial cell (EC) phenotype. Inflammatory chemokine secretion and VCAM1 expression were significantly increased in senescent ECs, resulting in tumor cell (TC) chemotaxis and TC/EC interactions. Meanwhile, EC senescence caused loosening of EC junctions, facilitating TC transmigration through the endothelial barrier. Sunitinib-induced senescent ECs also recruited cancer-associated myeloid cells to form a “pre-metastatic niche”-like microenvironment. Alterations at the molecular level and in the tissue environment ultimately led to an increase in distant metastasis. Conclusion: Although sunitinib was designed to target the EC directly, the increase in tumor metastasis may ironically be due to sunitinib “correctly” playing its role. Our findings suggest that we should carefully weigh the pros and cons before using sunitinib and other antiangiogenic drugs that directly target the ECs.

Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Widespread vascular hyperpermeability and a “cytokine storm” are two pathophysiological hallmarks of sepsis. Here, we show that intermedin (IMD), a member of the calcitonin family, alleviates organ injury and decreases mortality in septic mice by concurrently alleviating vascular leakage and inflammatory responses. IMD promotes the relocation of vascular endothelial cadherin through a Rab11-dependent pathway to dynamically repair the disrupted endothelial junction. Additionally, IMD decreases inflammatory responses by reducing macrophage infiltration via downregulating CCR2 expression. IMD peptide administration ameliorates organ injuries and significantly improves the survival of septic mice, and the experimental results correlate with the clinical data. Patients with high IMD levels exhibit a lower risk of shock, lower severity scores, and greatly improved survival outcomes than those with low IMD levels. Based on our data, IMD may be an important self-protective factor in response to sepsis.

This review attempts to unveil the possible mechanisms underlying how gut lymph affects lung and further gives rise to acute respiratory distress syndrome, as well as potential interventional targets under the condition of ischemia-reperfusion injury. We searched electronic databases including PubMed, MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, Web of Science, and Embase to identify relevant literatures published up to December 2019. We enrolled the literatures including the Mesh Terms of “gut lymph or intestinal lymph and acute lung injury or acute respiratory distress syndrome.” Gut is considered to be the origin of systemic inflammation and the engine of multiple organ distress syndrome in the field of critical care medicine, whereas gut lymph plays a pivotal role in initiation of ischemia-reperfusion injury-induced acute respiratory distress syndrome. In fact, in the having been established pathologic model of sepsis leading to multiple organ dysfunction named by Gut Lymph theory, a variety of literatures showed the position and role of changes in gut lymph components in the initiation of systemic inflammatory response, which allows us to screen out potential intervention targets to pave the way for future clinic and basic research.

Objective—: Intermedin plays an important role in vascular remodeling and significantly improves blood perfusion, but the precise mechanism remains unclear. Herein, we aimed to define whether vascular lumen enlargement is responsible for the intermedin-increased blood perfusion and explore the underlying cellular and molecular mechanisms. Approach and Results—: To study the role of intermedin, we generated the IMD-KO ( Adm2 ^−/− ) mice using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9) system. Intermedin significantly promoted vascular lumen enlargement in vitro (fibrin beads assay) and in vivo (murine retinas), which contributed to the improved blood perfusion in both physiological (retinal) and pathological (tumor) angiogenic models. We designed experiments to calculate the endothelial cell (EC) size and found that the lumen enlargement is because of EC proliferation but not because of a change in cell shape. ECs that construct vessel walls are considered quiescent cells because they are in a state of contact inhibition and show reduced responsiveness to VEGF (vascular endothelial growth factor). Using immunoprecipitation, Western blot assay, and fluorescent microscopy, we found that intermedin induced the formation of a signaling complex containing CRLR (calcitonin receptor-like receptor)/β-arr1 (β-arrestin1)/Src in ECs and promoted it internalizing into cytoplasm in a clathrin-dependent manner to activate downstream ERK1/2 (extracellular signal-regulated kinase 1/2). Importantly, this effect was not abrogated by cell–cell contacts of ECs. Through this mechanism, intermedin could reactivate the quiescent ECs to proliferate, resulting in continuous lumen expanding and a more effective blood perfusion. Conclusions—: Our findings suggest a novel mechanism that may explain how quiescent ECs overcome the contact inhibition and regain the ability to proliferate for continuous vascular lumen enlargement.

Objective: We aimed to determine whether the restrictive red-cell transfusion strategy was superior to the liberal one in reducing all-cause mortality in critically ill adults. Methods: The MEDLINE, EMBASE, PubMed, Web of Science, and Cochrane Library Central Register of Controlled Trials databases were searched from inception to January 2019 to identify meta-analyses or systematic reviews and published randomized controlled trials which were restrictive versus liberal blood transfusion with mortality as the endpoint in critically ill adults. We used two search routes whereby one search was restricted to systematic reviews, reviews, or meta-analysis, and the other was not restricted. There were no date restrictions, but language was limited to English and the population was restricted to critically ill adults. The data of study methods, participant characteristics, and outcomes were extracted and analyzed independently by 2 reviewers. The main outcome was all-cause mortality. Results: Through screening the obtained records, we enrolled 7 randomized clinical trials that included information on restrictive versus liberal red-cell transfusion and mortality of intensive care unit (ICU) patients. Involving a total of 7,363 ICU adult patients, ICU mortality (risk ratio [RR] 0.82, 95% confidence interval [CI] 0.62, 1.08, p = 0.15), 28/30-day mortality (RR 0.98, 95% CI 0.84, 1.13, p = 0.74), 60-day mortality (RR 1.01, 95% CI 0.87, 1.16, p = 0.91), 90-day mortality (RR 1.02, 95% CI 0.92, 1.14, p = 0.69), 120-day mortality (RR 1.29, 95% CI 0.67, 2.47, p = 0.44), and 180-day mortality (RR 0.91, 95% CI 0.75, 1.12, p = 0.38) were not statistically significantly different when the restrictive transfusion strategy was compared with the liberal transfusion strategy. However, we surprisingly discovered that 112 out of 469 (24%) patients who received a unit RBC transfusion when hemoglobin was less than 7 g/dL, and 142 out of 469 (30.3%) who received a unit of RBC transfused with hemoglobin less than 9 g/dL, had died during hospitalization (RR 0.79, 95% CI 0.64, 0.97, p = 0.03). The results showed that the restrictive transfusion strategy could decrease in-hospital mortality compared with the liberal transfusion strategy. It was safe to utilize a restrictive transfusion threshold of less than 7 g/dL in stable critically ill adults. Conclusions: In this study, we found that the restrictive red-cell transfusion strategy potentially reduced in-hospital mortality in critically ill adults with anemia compared with the liberal strategy.