To the Editor:The lung is the most frequent site of extrahepatic hepatocellular carcinoma(HCC)recurrence after liver transplantation(LT).Pulmonary metastasis from hepatocellular carcinoma(PM-HCC)carries a poor prognos...To the Editor:The lung is the most frequent site of extrahepatic hepatocellular carcinoma(HCC)recurrence after liver transplantation(LT).Pulmonary metastasis from hepatocellular carcinoma(PM-HCC)carries a poor prognosis as the patient could finally die of pulmonary failure secondary to the tumor despite maintaining ideal liver function.展开更多
Dear editor,Extracorporeal membrane oxygenation(ECMO)is a modality of extracorporeal life support that allows for temporary support in pulmonary and/or cardiac failure refractory to conventional therapy.[1]ECMO use ha...Dear editor,Extracorporeal membrane oxygenation(ECMO)is a modality of extracorporeal life support that allows for temporary support in pulmonary and/or cardiac failure refractory to conventional therapy.[1]ECMO use has been exponentially increasing over the last decade and is now considered a mainstream lifesaving treatment modality in critical care medicine.Many studies report ECMO use in patients with acute respiratory distress syndrome refractory to conventional clinical support,in-hospital cardiac arrest,and cardiogenic refractory shock.[1-3]Herein,we report the use of veno-arterial ECMO(VA-ECMO)in the first successful combined lung-liver transplantation(CLLT)patient in China.展开更多
BACKGROUND Lung transplantation is considered an effective method for treating patients with end-stage coronavirus disease 2019(COVID-19).The nurses play a pivotal role in lung transplantation for COVID-19 patients.CA...BACKGROUND Lung transplantation is considered an effective method for treating patients with end-stage coronavirus disease 2019(COVID-19).The nurses play a pivotal role in lung transplantation for COVID-19 patients.CASE SUMMARY Two elderly patients were admitted to the emergency department due to cough,and the nucleic acid test was positive.The patients were preliminarily diagnosed with COVID-19.The chest computed tomography scan revealed massive lung consolidation,and the patients did not improve after treatment with antiviral drugs,glucocorticoids,antibiotics,and other drugs.Under the support of pure oxygen in extracorporeal membrane oxygenation,the patients’oxygen levels were still poor,indicating that they were in the terminal stage of viral pneumonia.The patients underwent double-lung transplantation and received intraoperative care.The extracorporeal membrane oxygenation device was removed within a week of the surgical procedure,and the respiratory circulation of the patients were stabilized.CONCLUSION High-quality care for COVID-19 patients undergoing lung transplantation ensures patient safety during operation while protecting the safety of the medical staff.展开更多
<strong>Background:</strong> Extracorporeal membrane oxygenation (ECMO) is an effective adjuvant therapy for cardiopulmonary support during the period of lung transplantation (LTx). However, factors associ...<strong>Background:</strong> Extracorporeal membrane oxygenation (ECMO) is an effective adjuvant therapy for cardiopulmonary support during the period of lung transplantation (LTx). However, factors associated with the application of ECMO after LTx remain controversial. The purpose of this study is to clarify the risk factors of post-operative ECMO support and to evaluate the outcomes. <strong>Methods:</strong> It was a hospital, single-center, retrospective study. 266 patients underwent LTx supported by ECMO were included. According to whether or not the patients received continourly ECMO support after the surgery, the enrolled patients were further divided into intra-operative ECMO group (group I, 105 cases) and post-operative ECMO group (group P, 161 cases). The peri-operative data of the donors and recipients were collected. The independent risk factors associated with post-operative ECMO support during LTx were identified. The relationship between primary graft dysfunction (PGD)/post-operative survival and duration of ECMO support was also analyzed. <strong>Results:</strong> Prolonged donor ventilation ≥ 5 days, pre-operative recipient mechanical ventilation, bilateral lung transplantation (BLT), veno-venous (V-V) ECMO and PGD in recipient were independent risk factors for post-operative ECMO support. The risk of PGD and post-operative death increased along with the increase of ECMO bypass time, and the mortality risk in group P was 2.33 (95% confidence interval: 1.16 - 4.67) times as that in group I. <strong>Conclusions:</strong> Mechanical ventilation for donor ≥ 5 days, pre-operative mechanical ventilation, BLT, V-V-ECMO and PGD in recipient were independent risk factors for post-operative ECMO support after LTx, and post-operative ECMO could not reduce recipients’ hospital mortality.展开更多
Introduction Organ transplantation increases survival and improves qual-ity of life to many patients with end-stage organ failure.Or-gan shortage is a worldwide problem that restricts organ trans-plantation[1].Organ p...Introduction Organ transplantation increases survival and improves qual-ity of life to many patients with end-stage organ failure.Or-gan shortage is a worldwide problem that restricts organ trans-plantation[1].Organ procurement and preservation as well as ischemia-reperfusion injury(IRI)after transplantation are the im-portant factors affecting prognosis of recipients.Since the de-velopment of organ transplantation technology in the 20th cen-tury,organ protection technology has been a most promising con-cept in this field.Organ preservation solutions such as the Collins solution,University of Wisconsin(UW)solution,and histidine-tryptophan-ketoglutarate(HTK)solution were developed sequen-tially[2],which developed rapidly in static cold storage(SCS)tech-niques.SCS remains the standard preservation technique for organ transplantation[2].展开更多
The development of precise and sensitive electrophysiological recording platforms holds the utmost importance for research in the fields of cardiology and neuroscience.In recent years,active micro/nano-bioelectronic d...The development of precise and sensitive electrophysiological recording platforms holds the utmost importance for research in the fields of cardiology and neuroscience.In recent years,active micro/nano-bioelectronic devices have undergone significant advancements,thereby facilitating the study of electrophysiology.The distinctive configuration and exceptional functionality of these active micro-nano-collaborative bioelectronic devices offer the potential for the recording of high-fidelity action potential signals on a large scale.In this paper,we review three-dimensional active nano-transistors and planar active micro-transistors in terms of their applications in electroexcitable cells,focusing on the evaluation of the effects of active micro/nano-bioelectronic devices on electrophysiological signals.Looking forward to the possibilities,challenges,and wide prospects of active micro-nano-devices,we expect to advance their progress to satisfy the demands of theoretical investigations and medical implementations within the domains of cardiology and neuroscience research.展开更多
BACKGROUND Rearrangements of the anaplastic lymphoma kinase(ALK)gene(ALK-positive)represent an oncogenic driver in approximately 3%-5%of non-small-lung cancer(NSCLC)patients.Sarcoidosis is a multisystem disease,and it...BACKGROUND Rearrangements of the anaplastic lymphoma kinase(ALK)gene(ALK-positive)represent an oncogenic driver in approximately 3%-5%of non-small-lung cancer(NSCLC)patients.Sarcoidosis is a multisystem disease,and its reported incidence in Asia is 1 or less per 100000 people per year.The co-occurrence of sarcoidosis and ALK-positive NSCLC is rare,and ALK-positive lung cancer is likely to spread quickly.Therefore,the co-occurrence of sarcoidosis is more easily misdiagnosed as metastatic lung cancer by radiological examination.CASE SUMMARY A 50-year-old man had a nodule in the left superior lobe,many small nodules in left superior and right lungs,and enlarged bilateral hilar,mediastinal,and right supraclavicular lymph nodes.Computed tomography-guided pulmonary biopsy of the nodule in the left superior lobe revealed echinoderm microtubuleassociated protein-like 4 gene-ALK positive NSCLC with concomitant noncaseating granuloma.This patient was treated with crizotinib.Thirty days later,a chest computed tomography scan revealed a dramatic decrease in the size of the left superior lobe nodule;however,the lesions in the right lung progressed.The right supraclavicular lymph nodes showed granulomas,and no tumor cells were identified in the specimens. The angiotensin-converting enzyme level was high.After 1 wk of methylprednisolone treatment, a significant response of all lesionswas revealed. Following radical resection of the lung cancer, noncaseatinggranulomas were observed in both lung tissues and lymph nodes, which resultedin a diagnosis of echinoderm microtubule-associated protein-like 4-ALK positiveNSCLC accompanied with sarcoidosis.CONCLUSIONOur experience illustrates that pathological evidence is needed to confirmmetastatic disease, especially when some suspected metastatic lesions arenegative for malignancy.展开更多
Ventilator-assisted ventilation and lung transplantation are the final treatments for the patients with end-stage respiratory failure.A patient,who has been diagnosed as end-stage respiratory failure and received trac...Ventilator-assisted ventilation and lung transplantation are the final treatments for the patients with end-stage respiratory failure.A patient,who has been diagnosed as end-stage respiratory failure and received tracheal intubation with mechanical ventilation,received the treatment of Chinese herbal medicine on the principle of TCM and got some recovery gradually.After two months,the patient got rid of mechanical ventilation successfully.This case implies that TCM will be an alternative treatment for the patients with the similar conditions.展开更多
Background:Acute kidney injury(AKI)is a common and serious complication following lung transplantation(LTx),and it is associated with high mortality and morbidity.This study assessed the incidence of AKI after LTx and...Background:Acute kidney injury(AKI)is a common and serious complication following lung transplantation(LTx),and it is associated with high mortality and morbidity.This study assessed the incidence of AKI after LTx and analyzed the associated perioperative factors and clinical outcomes.Methods:This retrospective study included all adult LTx recipients at the China-Japan Friendship Hospital in Beijing between March 2017 and December 2019.The outcomes were AKI incidence,risk factors,mortality,and kidney recovery.Multivariate analysis was performed to identify independent risk factors.Survival analysis was presented using the Kaplan-Meier curves.Results:AKI occurred in 137 of the 191 patients(71.7%),with transient AKI in 43(22.5%)and persistent AKI in 94(49.2%).AKI stage 1 occurred in 27/191(14.1%),stage 2 in 46/191(24.1%),and stage 3 in 64/191(33.5%)of the AKI patients.Renal replacement therapy(RRT)was administered to 35/191(18.3%)of the patients.Male sex,older age,mechanical ventilation(MV),severe hypotension,septic shock,multiple organ dysfunction(MODS),prolonged extracorporeal membrane oxygenation(ECMO),reintubation,and nephrotoxic agents were associated with AKI(P<0.050).Persistent AKI was independently associated with pre-operative pulmonary hypertension,severe hypotension,post-operative MODS,and nephrotoxic agents.Severe hypotension,septic shock,MODS,reintubation,prolonged MV,and ECMO during or after LTx were related to severe AKI(stage 3)(P<0.050).Patients with persistent and severe AKI had a significantly longer duration of MV,longer duration in the intensive care unit(ICU),worse downstream kidney function,and reduced survival(P<0.050).Conclusions:AKI is common after LTx,but the pathogenic mechanism of AKI is complicated,and prerenal causes are important.Persistent and severe AKI were associated with poor short-and long-term kidney function and reduced survival in LTx patients.展开更多
To the Editor: Appropriate donor-to-recipient size matching is of crucial importance in lung transplantation. Although tailoring of the lung has been described as a successful means of overcoming size disparities, its...To the Editor: Appropriate donor-to-recipient size matching is of crucial importance in lung transplantation. Although tailoring of the lung has been described as a successful means of overcoming size disparities, its merits and demerits remain unclear. Here, we present a case of recurrent hypoxemia after unmatched single lung transplantation.展开更多
To the Editor:Organ donation after the citizen’s death program was fully launched in China in 2015.According to the allocation regulations of donated organs,all donated lungs must be allocated through the China Organ...To the Editor:Organ donation after the citizen’s death program was fully launched in China in 2015.According to the allocation regulations of donated organs,all donated lungs must be allocated through the China Organ Transplant Response System(COTRS,www.cot.org.cn).[1]To fully optimize the implementation of organ transportation sharing policy and coordinate multiple government departments and social groups involved in the process,the"Green Channel of Human Organ Transport(GCHOT)"was established on May 6th,2016 in China[Supplementary Figure 1,http://links.lww.com/CM9/A431].[2]In this study,we reviewed and compared the status of lung transportation between the pre-and post-GCHOT periods based on data collected from the largest lung transplantation(LT)center in Wuxi,Jiangsu,China,with the aim of introducing the detailed process and implementation of GCHOT in China.展开更多
Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PD...Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A–D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA–CREB–BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.展开更多
文摘To the Editor:The lung is the most frequent site of extrahepatic hepatocellular carcinoma(HCC)recurrence after liver transplantation(LT).Pulmonary metastasis from hepatocellular carcinoma(PM-HCC)carries a poor prognosis as the patient could finally die of pulmonary failure secondary to the tumor despite maintaining ideal liver function.
文摘Dear editor,Extracorporeal membrane oxygenation(ECMO)is a modality of extracorporeal life support that allows for temporary support in pulmonary and/or cardiac failure refractory to conventional therapy.[1]ECMO use has been exponentially increasing over the last decade and is now considered a mainstream lifesaving treatment modality in critical care medicine.Many studies report ECMO use in patients with acute respiratory distress syndrome refractory to conventional clinical support,in-hospital cardiac arrest,and cardiogenic refractory shock.[1-3]Herein,we report the use of veno-arterial ECMO(VA-ECMO)in the first successful combined lung-liver transplantation(CLLT)patient in China.
基金Supported by Medical and Health Science and Technology Project of Zhejiang Province(Fund Project No.2019KY394).
文摘BACKGROUND Lung transplantation is considered an effective method for treating patients with end-stage coronavirus disease 2019(COVID-19).The nurses play a pivotal role in lung transplantation for COVID-19 patients.CASE SUMMARY Two elderly patients were admitted to the emergency department due to cough,and the nucleic acid test was positive.The patients were preliminarily diagnosed with COVID-19.The chest computed tomography scan revealed massive lung consolidation,and the patients did not improve after treatment with antiviral drugs,glucocorticoids,antibiotics,and other drugs.Under the support of pure oxygen in extracorporeal membrane oxygenation,the patients’oxygen levels were still poor,indicating that they were in the terminal stage of viral pneumonia.The patients underwent double-lung transplantation and received intraoperative care.The extracorporeal membrane oxygenation device was removed within a week of the surgical procedure,and the respiratory circulation of the patients were stabilized.CONCLUSION High-quality care for COVID-19 patients undergoing lung transplantation ensures patient safety during operation while protecting the safety of the medical staff.
文摘<strong>Background:</strong> Extracorporeal membrane oxygenation (ECMO) is an effective adjuvant therapy for cardiopulmonary support during the period of lung transplantation (LTx). However, factors associated with the application of ECMO after LTx remain controversial. The purpose of this study is to clarify the risk factors of post-operative ECMO support and to evaluate the outcomes. <strong>Methods:</strong> It was a hospital, single-center, retrospective study. 266 patients underwent LTx supported by ECMO were included. According to whether or not the patients received continourly ECMO support after the surgery, the enrolled patients were further divided into intra-operative ECMO group (group I, 105 cases) and post-operative ECMO group (group P, 161 cases). The peri-operative data of the donors and recipients were collected. The independent risk factors associated with post-operative ECMO support during LTx were identified. The relationship between primary graft dysfunction (PGD)/post-operative survival and duration of ECMO support was also analyzed. <strong>Results:</strong> Prolonged donor ventilation ≥ 5 days, pre-operative recipient mechanical ventilation, bilateral lung transplantation (BLT), veno-venous (V-V) ECMO and PGD in recipient were independent risk factors for post-operative ECMO support. The risk of PGD and post-operative death increased along with the increase of ECMO bypass time, and the mortality risk in group P was 2.33 (95% confidence interval: 1.16 - 4.67) times as that in group I. <strong>Conclusions:</strong> Mechanical ventilation for donor ≥ 5 days, pre-operative mechanical ventilation, BLT, V-V-ECMO and PGD in recipient were independent risk factors for post-operative ECMO support after LTx, and post-operative ECMO could not reduce recipients’ hospital mortality.
基金Major Science and Technology Projects of Hainan Province(ZDKJ2019009)Research Project of Ji’nan Microecological Biomedicine Shandong Labora-tory(JNL-2022002A and JNL-2022023C)+3 种基金Public Projects of Zhe-jiang Province(LGF21H030006)Research Unit Project of Chinese Academy of Medical Sciences(2019-I2M-5-030)the National Natu-ral Science Foundation of China(81721091,62073211)the Na-tional S&T Major Project for Infectious Diseases(2017ZX10203205).
文摘Introduction Organ transplantation increases survival and improves qual-ity of life to many patients with end-stage organ failure.Or-gan shortage is a worldwide problem that restricts organ trans-plantation[1].Organ procurement and preservation as well as ischemia-reperfusion injury(IRI)after transplantation are the im-portant factors affecting prognosis of recipients.Since the de-velopment of organ transplantation technology in the 20th cen-tury,organ protection technology has been a most promising con-cept in this field.Organ preservation solutions such as the Collins solution,University of Wisconsin(UW)solution,and histidine-tryptophan-ketoglutarate(HTK)solution were developed sequen-tially[2],which developed rapidly in static cold storage(SCS)tech-niques.SCS remains the standard preservation technique for organ transplantation[2].
基金The work is supported in part by the National Natural Science Foundation of China(Grant Nos.62171483,82061148011)Zhejiang Provincial Natural Science Foundation of China(Grant No.LZ23F010004)+1 种基金Hangzhou Agricultural and Social Development Research Key Project(Grant No.20231203A08)Doctoral Initiation Program of the Tenth Affiliated Hospital,Southern Medical University(Grant No.K202308).
文摘The development of precise and sensitive electrophysiological recording platforms holds the utmost importance for research in the fields of cardiology and neuroscience.In recent years,active micro/nano-bioelectronic devices have undergone significant advancements,thereby facilitating the study of electrophysiology.The distinctive configuration and exceptional functionality of these active micro-nano-collaborative bioelectronic devices offer the potential for the recording of high-fidelity action potential signals on a large scale.In this paper,we review three-dimensional active nano-transistors and planar active micro-transistors in terms of their applications in electroexcitable cells,focusing on the evaluation of the effects of active micro/nano-bioelectronic devices on electrophysiological signals.Looking forward to the possibilities,challenges,and wide prospects of active micro-nano-devices,we expect to advance their progress to satisfy the demands of theoretical investigations and medical implementations within the domains of cardiology and neuroscience research.
基金The Zhejiang Provincial Natural Science Foundation of China,No.LQ17H160005.
文摘BACKGROUND Rearrangements of the anaplastic lymphoma kinase(ALK)gene(ALK-positive)represent an oncogenic driver in approximately 3%-5%of non-small-lung cancer(NSCLC)patients.Sarcoidosis is a multisystem disease,and its reported incidence in Asia is 1 or less per 100000 people per year.The co-occurrence of sarcoidosis and ALK-positive NSCLC is rare,and ALK-positive lung cancer is likely to spread quickly.Therefore,the co-occurrence of sarcoidosis is more easily misdiagnosed as metastatic lung cancer by radiological examination.CASE SUMMARY A 50-year-old man had a nodule in the left superior lobe,many small nodules in left superior and right lungs,and enlarged bilateral hilar,mediastinal,and right supraclavicular lymph nodes.Computed tomography-guided pulmonary biopsy of the nodule in the left superior lobe revealed echinoderm microtubuleassociated protein-like 4 gene-ALK positive NSCLC with concomitant noncaseating granuloma.This patient was treated with crizotinib.Thirty days later,a chest computed tomography scan revealed a dramatic decrease in the size of the left superior lobe nodule;however,the lesions in the right lung progressed.The right supraclavicular lymph nodes showed granulomas,and no tumor cells were identified in the specimens. The angiotensin-converting enzyme level was high.After 1 wk of methylprednisolone treatment, a significant response of all lesionswas revealed. Following radical resection of the lung cancer, noncaseatinggranulomas were observed in both lung tissues and lymph nodes, which resultedin a diagnosis of echinoderm microtubule-associated protein-like 4-ALK positiveNSCLC accompanied with sarcoidosis.CONCLUSIONOur experience illustrates that pathological evidence is needed to confirmmetastatic disease, especially when some suspected metastatic lesions arenegative for malignancy.
文摘Ventilator-assisted ventilation and lung transplantation are the final treatments for the patients with end-stage respiratory failure.A patient,who has been diagnosed as end-stage respiratory failure and received tracheal intubation with mechanical ventilation,received the treatment of Chinese herbal medicine on the principle of TCM and got some recovery gradually.After two months,the patient got rid of mechanical ventilation successfully.This case implies that TCM will be an alternative treatment for the patients with the similar conditions.
基金This work was supported by the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2019PT320020).
文摘Background:Acute kidney injury(AKI)is a common and serious complication following lung transplantation(LTx),and it is associated with high mortality and morbidity.This study assessed the incidence of AKI after LTx and analyzed the associated perioperative factors and clinical outcomes.Methods:This retrospective study included all adult LTx recipients at the China-Japan Friendship Hospital in Beijing between March 2017 and December 2019.The outcomes were AKI incidence,risk factors,mortality,and kidney recovery.Multivariate analysis was performed to identify independent risk factors.Survival analysis was presented using the Kaplan-Meier curves.Results:AKI occurred in 137 of the 191 patients(71.7%),with transient AKI in 43(22.5%)and persistent AKI in 94(49.2%).AKI stage 1 occurred in 27/191(14.1%),stage 2 in 46/191(24.1%),and stage 3 in 64/191(33.5%)of the AKI patients.Renal replacement therapy(RRT)was administered to 35/191(18.3%)of the patients.Male sex,older age,mechanical ventilation(MV),severe hypotension,septic shock,multiple organ dysfunction(MODS),prolonged extracorporeal membrane oxygenation(ECMO),reintubation,and nephrotoxic agents were associated with AKI(P<0.050).Persistent AKI was independently associated with pre-operative pulmonary hypertension,severe hypotension,post-operative MODS,and nephrotoxic agents.Severe hypotension,septic shock,MODS,reintubation,prolonged MV,and ECMO during or after LTx were related to severe AKI(stage 3)(P<0.050).Patients with persistent and severe AKI had a significantly longer duration of MV,longer duration in the intensive care unit(ICU),worse downstream kidney function,and reduced survival(P<0.050).Conclusions:AKI is common after LTx,but the pathogenic mechanism of AKI is complicated,and prerenal causes are important.Persistent and severe AKI were associated with poor short-and long-term kidney function and reduced survival in LTx patients.
文摘To the Editor: Appropriate donor-to-recipient size matching is of crucial importance in lung transplantation. Although tailoring of the lung has been described as a successful means of overcoming size disparities, its merits and demerits remain unclear. Here, we present a case of recurrent hypoxemia after unmatched single lung transplantation.
基金supported by a grant from the Special Research Project on Human Organ Donation in China(No.CODMP2017016)。
文摘To the Editor:Organ donation after the citizen’s death program was fully launched in China in 2015.According to the allocation regulations of donated organs,all donated lungs must be allocated through the China Organ Transplant Response System(COTRS,www.cot.org.cn).[1]To fully optimize the implementation of organ transportation sharing policy and coordinate multiple government departments and social groups involved in the process,the"Green Channel of Human Organ Transport(GCHOT)"was established on May 6th,2016 in China[Supplementary Figure 1,http://links.lww.com/CM9/A431].[2]In this study,we reviewed and compared the status of lung transportation between the pre-and post-GCHOT periods based on data collected from the largest lung transplantation(LT)center in Wuxi,Jiangsu,China,with the aim of introducing the detailed process and implementation of GCHOT in China.
基金This work was supported by Beijing Natural Science Foundation[Z220019 to Jing Wang,China]National High Level of Hospital Clinical Research Funding[2022-PUMCH-D-002 to Jing Wang,China]+3 种基金National Key Research and Development Program of China Grants[2019YFA0801703 and 2019YFA0801804 to Jing Wang]Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences[2022-I2M-JB-007 to Chen Wang,2021-I2M-1-016 to Hongmei Zhao,2021-I2M-1-049 to Jing Wang,2021-I2M-1-005 to Yanjiang Xing,China]Haihe Laboratory of Cell Ecosystem Innovation Fund[22HHXBSS00010 to Jing Wang,China]National Natural Science Foundation of China[82241004 to Jing Wang].
文摘Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A–D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA–CREB–BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.