Acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are common life-threatening lung diseases associated with acute and severe inflammation.Both have high mortality rates,and despite decades of research...Acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are common life-threatening lung diseases associated with acute and severe inflammation.Both have high mortality rates,and despite decades of research on clinical ALI/ARDS,there are no effective therapeutic strategies.Disruption of alveolar-capillary barrier integrity or activation of inflammatory responses leads to lung inflammation and injury.Recently,studies on the role of extracellular vesicles(EVs)in regulating normal and pathophysiologic cell activities,including inflammation and injury responses,have attracted attention.Injured and dysfunctional cells often secrete EVs into serum or bronchoalveolar lavage fluid with altered cargoes,which can be used to diagnose and predict the development of ALI/ARDS.EVs secreted by mesenchymal stem cells can also attenuate inflammatory reactions associated with cell dysfunction and injury to preserve or restore cell function,and thereby promote cell proliferation and tissue regeneration.This review focuses on the roles of EVs in the pathogenesis of pulmonary inflammation,particularly ALI/ARDS.展开更多
The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia ...The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.展开更多
Macrophages are typically identified as classically activated(M1) macrophages and alternatively activated(M2) macrophages,which respectively exhibit pro-and anti-inflammatory phenotypes,and the balance between these t...Macrophages are typically identified as classically activated(M1) macrophages and alternatively activated(M2) macrophages,which respectively exhibit pro-and anti-inflammatory phenotypes,and the balance between these two subtypes plays a critical role in the regulation of tissue inflammation,injury,and repair processes.Recent studies indicate that tissue cells and macrophages interact via the release of small extracellular vesicles(EVs) in processes where EVs released by stressed tissue cells can promote the activation and polarization of adjacent macrophages which can in turn release EVs and factors that can promote cell stress and tissue inflammation and injury and vice versa.This review discusses the roles of such EVs in resulating such interactions to influence tissue inflammation and injury in a number of acute and chronic inflammatory disease conditions,and the potential applications,advantage and concerns for using EV-based therapeutic approaches to treat such conditions,including their potential role of drug carriers for the treatment of infectious diseases.展开更多
Identification of epitopes targeted following virus infection or vaccination can guide vaccine design and development of therapeutic interventions targeting functional sites,but can be laborious.Herein,we employed pep...Identification of epitopes targeted following virus infection or vaccination can guide vaccine design and development of therapeutic interventions targeting functional sites,but can be laborious.Herein,we employed peptide microarrays to map linear peptide epitopes(LPEs)recognized following SARS-CoV-2 infetion and vaccination.LPEs detected by nonhuman primate(NHP)and patient IgMs after SARS-CoV-2 infection extensively overlapped,localized to functionally important virus regions,and aligned with reported neutralizing antibody binding sies.Similar LPE overlap occurred atfter infection and vaccination,with LPE clusters specifc to each stimulus,where strong and conserved LPEs mapping to sites known or likely to inhibit spike protein function.Vaccine-specifc LPEs tended to map to sites known or likely to be afected by structural changes induced by the proline substitutions in the mRNA vaccine's S protein.Mapping LPEs to regions of known functional importance in this manner may acelerate vaccine evaluation and discovery of targets for sile secific therapeutic interventions.展开更多
基金This work was supported by the Weatherhead Endowment Fund
文摘Acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are common life-threatening lung diseases associated with acute and severe inflammation.Both have high mortality rates,and despite decades of research on clinical ALI/ARDS,there are no effective therapeutic strategies.Disruption of alveolar-capillary barrier integrity or activation of inflammatory responses leads to lung inflammation and injury.Recently,studies on the role of extracellular vesicles(EVs)in regulating normal and pathophysiologic cell activities,including inflammation and injury responses,have attracted attention.Injured and dysfunctional cells often secrete EVs into serum or bronchoalveolar lavage fluid with altered cargoes,which can be used to diagnose and predict the development of ALI/ARDS.EVs secreted by mesenchymal stem cells can also attenuate inflammatory reactions associated with cell dysfunction and injury to preserve or restore cell function,and thereby promote cell proliferation and tissue regeneration.This review focuses on the roles of EVs in the pathogenesis of pulmonary inflammation,particularly ALI/ARDS.
基金the Arizona Biomedical Research Commission(ABRC)young investigator awardthe Fred Hutchinson Cancer Research Center(0000917241)Tulane University Startup fund。
文摘The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.
基金the support from Weatherhead Presidential Endowment Fund (USA)。
文摘Macrophages are typically identified as classically activated(M1) macrophages and alternatively activated(M2) macrophages,which respectively exhibit pro-and anti-inflammatory phenotypes,and the balance between these two subtypes plays a critical role in the regulation of tissue inflammation,injury,and repair processes.Recent studies indicate that tissue cells and macrophages interact via the release of small extracellular vesicles(EVs) in processes where EVs released by stressed tissue cells can promote the activation and polarization of adjacent macrophages which can in turn release EVs and factors that can promote cell stress and tissue inflammation and injury and vice versa.This review discusses the roles of such EVs in resulating such interactions to influence tissue inflammation and injury in a number of acute and chronic inflammatory disease conditions,and the potential applications,advantage and concerns for using EV-based therapeutic approaches to treat such conditions,including their potential role of drug carriers for the treatment of infectious diseases.
基金supported by the Department of Defense(grant number W8IxwH19i0926)National Institute of Allergy and Infectious Diseases contract(grant number_HHSN2722017000331)+1 种基金National Institute of Child Health and Human Development grant(grant numbers R01HD090927 and R01HDi03511)National Center for Research Resources and the Ofice of Research Infrastructure Programs(grant numbers OD011104).
文摘Identification of epitopes targeted following virus infection or vaccination can guide vaccine design and development of therapeutic interventions targeting functional sites,but can be laborious.Herein,we employed peptide microarrays to map linear peptide epitopes(LPEs)recognized following SARS-CoV-2 infetion and vaccination.LPEs detected by nonhuman primate(NHP)and patient IgMs after SARS-CoV-2 infection extensively overlapped,localized to functionally important virus regions,and aligned with reported neutralizing antibody binding sies.Similar LPE overlap occurred atfter infection and vaccination,with LPE clusters specifc to each stimulus,where strong and conserved LPEs mapping to sites known or likely to inhibit spike protein function.Vaccine-specifc LPEs tended to map to sites known or likely to be afected by structural changes induced by the proline substitutions in the mRNA vaccine's S protein.Mapping LPEs to regions of known functional importance in this manner may acelerate vaccine evaluation and discovery of targets for sile secific therapeutic interventions.
