Sepsis is a common complication of combat injuries and trauma,and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.It is also one of the significant causes of deat...Sepsis is a common complication of combat injuries and trauma,and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.It is also one of the significant causes of death and increased health care costs in modern intensive care units.The use of antibiotics,fluid resuscitation,and organ support therapy have limited prognostic impact in patients with sepsis.Although its pathophysiology remains elusive,immunosuppression is now recognized as one of the major causes of septic death.Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis.It is characterized by the release of antiinflammatory cytokines,abnormal death of immune effector cells,hyperproliferation of immune suppressor cells,and expression of immune checkpoints.By targeting immunosuppression,especially with immune checkpoint inhibitors,preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance.Here,we comprehensively discuss recent findings on the mechanisms,regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.展开更多
Purpose:This study aims to elucidate the electrotaxis response of alveolar epithelial cells(AECs)in direct-current electric fields(EFs),explore the impact of EFs on the cell fate of AECs,and lay the foundation for fut...Purpose:This study aims to elucidate the electrotaxis response of alveolar epithelial cells(AECs)in direct-current electric fields(EFs),explore the impact of EFs on the cell fate of AECs,and lay the foundation for future exploitation of EFs for the treatment of acute lung injury.Methods:AECs were extracted from rat lung tissues using magnetic-activated cell sorting.To elucidate the electrotaxis responses of AECs,different voltages of EFs(0,50,100,and 200 mV/mm)were applied to two types of AECs,respectively.Cell migrations were recorded and trajectories were pooled to better demonstrate cellular activities through graphs.Cell directionality was calculated as the cosine value of the angle formed by the EF vector and cell migration.To further demonstrate the impact of EFs on the pulmonary tissue,the human bronchial epithelial cells transformed with Ad12-SV402B(BEAS-2B cells)were obtained and experimented under the same conditions as AECs.To determine the influence on cell fate,cells underwent electric stimulation were collected to perform Western blot analysis.Results:The successful separation and culturing of AECs were confirmed through immunofluorescence staining.Compared with the control,AECs in EFs demonstrated a significant directionality in a voltage-dependent way.In general,type I alveolar epithelial cells migrated faster than type II alveolar epithelial cells,and under EFs,these two types of cells exhibited different response threshold.For type II alveolar epithelial cells,only EFs at 200 mV/mm resulted a significant difference to the velocity,whereas for,EFs at both 100 mV/mm and 200 mV/mm gave rise to a significant difference.Western blotting suggested that EFs led to an increased expression of a AKT and myeloid leukemia 1 and a decreased expression of Bcl-2-associated X protein and Bcl-2-like protein 11.Conclusion:EFs could guide and accelerate the directional migration of AECs and exert antiapoptotic effects,which indicated that EFs are important biophysical signals in the re-epithelialization of alveolar epithelium in lung injury.展开更多
Sepsis,defined as life-threatening organ failure caused by a dysregulated host response to severe infection,is a major cause of death among intensive care unit patients.Therapies targeting on immunomodulatory is a new...Sepsis,defined as life-threatening organ failure caused by a dysregulated host response to severe infection,is a major cause of death among intensive care unit patients.Therapies targeting on immunomodulatory is a new research field in sepsis treatment.B-and T-lymphocyte attenuator(BTLA)is an inhibitory costimulatory factor molecule of B and T lymphocytes.Studies have shown that elevated expression of BTLA in lymphocytes can reduce mortality in sepsis,but its regulatory compounds and the underlying mechanism remains to be elucidated.Here,we show that treatment with CP-673451 significantly decreases mortality of septic mouse.CP-673451 is a PDGFR kinase inhibitor which can promote the expression of BTLA,inhibit the release of chemokines such as CXCL13,and reduce first the chemotaxis of B cells to the peripheral blood and vital organs.CP-673451 also inhibits both the release of cytokines and chemokines such as IL-1β,IL-6,IL-10,TNF-α,CCL1,CCL2 and CCL7 and reduces both the chemotactic ability of T cells.This suggests that CP-673451 may prevent septic death by inhibiting lymphocyte chemotaxis and alleviating“cytokine storm”.In conclusion,our study provides a new therapeutic target and an effective compound for sepsis treatment.展开更多
基金supported by the National Natural Science Foundation of China(82222038,82020108021 and 82260372)the Chongqing Special Project for Academicians(cstc2020yszx-jcyjX0004)the Chongqing Outstanding Youth Foundation and Science Foundation for Outstanding Youth of the Army Medical Centre(2019CXJSB004)。
文摘Sepsis is a common complication of combat injuries and trauma,and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.It is also one of the significant causes of death and increased health care costs in modern intensive care units.The use of antibiotics,fluid resuscitation,and organ support therapy have limited prognostic impact in patients with sepsis.Although its pathophysiology remains elusive,immunosuppression is now recognized as one of the major causes of septic death.Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis.It is characterized by the release of antiinflammatory cytokines,abnormal death of immune effector cells,hyperproliferation of immune suppressor cells,and expression of immune checkpoints.By targeting immunosuppression,especially with immune checkpoint inhibitors,preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance.Here,we comprehensively discuss recent findings on the mechanisms,regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.
基金National Natural Science Foundation of China(82272908,81672287,82222038)Natural Science Foundation of Chongqing(CSTB2022NSCQ-MSX1110)+1 种基金Open Project Program of the State Key Laboratory of Trauma,Burn and Combined Injury(SKLYQ202102,SKLKF2022011)Daping Hospital of Army Medical University(2019CXJSB004,2019CXJSC024)。
文摘Purpose:This study aims to elucidate the electrotaxis response of alveolar epithelial cells(AECs)in direct-current electric fields(EFs),explore the impact of EFs on the cell fate of AECs,and lay the foundation for future exploitation of EFs for the treatment of acute lung injury.Methods:AECs were extracted from rat lung tissues using magnetic-activated cell sorting.To elucidate the electrotaxis responses of AECs,different voltages of EFs(0,50,100,and 200 mV/mm)were applied to two types of AECs,respectively.Cell migrations were recorded and trajectories were pooled to better demonstrate cellular activities through graphs.Cell directionality was calculated as the cosine value of the angle formed by the EF vector and cell migration.To further demonstrate the impact of EFs on the pulmonary tissue,the human bronchial epithelial cells transformed with Ad12-SV402B(BEAS-2B cells)were obtained and experimented under the same conditions as AECs.To determine the influence on cell fate,cells underwent electric stimulation were collected to perform Western blot analysis.Results:The successful separation and culturing of AECs were confirmed through immunofluorescence staining.Compared with the control,AECs in EFs demonstrated a significant directionality in a voltage-dependent way.In general,type I alveolar epithelial cells migrated faster than type II alveolar epithelial cells,and under EFs,these two types of cells exhibited different response threshold.For type II alveolar epithelial cells,only EFs at 200 mV/mm resulted a significant difference to the velocity,whereas for,EFs at both 100 mV/mm and 200 mV/mm gave rise to a significant difference.Western blotting suggested that EFs led to an increased expression of a AKT and myeloid leukemia 1 and a decreased expression of Bcl-2-associated X protein and Bcl-2-like protein 11.Conclusion:EFs could guide and accelerate the directional migration of AECs and exert antiapoptotic effects,which indicated that EFs are important biophysical signals in the re-epithelialization of alveolar epithelium in lung injury.
基金supported by the National Natural Science Foundation of China(82020108021)the Chongqing Special Project for Academicians(cstc2020yszx-jcyj X0004)+3 种基金the Project of the TraumaBurns and Combined Injury State Key Laboratory(SKLYQ201901,SKLKF201802)the Training Plan of the Innovation Ability of Military Medical Frontier Research(2019CXJSB014,2019CXJSB004)the Project of the Science and Technology Fund of Guizhou Provincial Department of Health(gzwjkj2020-1-106)。
文摘Sepsis,defined as life-threatening organ failure caused by a dysregulated host response to severe infection,is a major cause of death among intensive care unit patients.Therapies targeting on immunomodulatory is a new research field in sepsis treatment.B-and T-lymphocyte attenuator(BTLA)is an inhibitory costimulatory factor molecule of B and T lymphocytes.Studies have shown that elevated expression of BTLA in lymphocytes can reduce mortality in sepsis,but its regulatory compounds and the underlying mechanism remains to be elucidated.Here,we show that treatment with CP-673451 significantly decreases mortality of septic mouse.CP-673451 is a PDGFR kinase inhibitor which can promote the expression of BTLA,inhibit the release of chemokines such as CXCL13,and reduce first the chemotaxis of B cells to the peripheral blood and vital organs.CP-673451 also inhibits both the release of cytokines and chemokines such as IL-1β,IL-6,IL-10,TNF-α,CCL1,CCL2 and CCL7 and reduces both the chemotactic ability of T cells.This suggests that CP-673451 may prevent septic death by inhibiting lymphocyte chemotaxis and alleviating“cytokine storm”.In conclusion,our study provides a new therapeutic target and an effective compound for sepsis treatment.
