Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms
Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samp...
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| Veröffentlicht in: | American journal of physiology. Lung cellular and molecular physiology 2023-02, Vol.324 (2), p.L89-L101 |
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| container_title | American journal of physiology. Lung cellular and molecular physiology |
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| creator | Li, De-Bao Xu, Xiu-Xia Hu, Yu-Qing Cui, Qing Xiao, Ying-Ying Sun, Si-Juan Chen, Li-Jun Ye, Lin-Cai Sun, Qi |
| description | Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of patients with CHD with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia. |
| doi_str_mv | 10.1152/ajplung.00195.2022 |
| format | Article |
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However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of patients with CHD with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia.</description><identifier>ISSN: 1040-0605</identifier><identifier>EISSN: 1522-1504</identifier><identifier>DOI: 10.1152/ajplung.00195.2022</identifier><identifier>PMID: 36472329</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Alveoli ; Animals ; Animals, Newborn ; Biological activity ; Blood flow ; Body weight ; Body weight loss ; Cardiovascular disease ; Cardiovascular diseases ; Child ; Congenital diseases ; Cyanosis ; Cyclosporins ; Dysplasia ; Flow cytometry ; Gene sequencing ; Heart Defects, Congenital - complications ; Heart Defects, Congenital - metabolism ; Heart Defects, Congenital - pathology ; Heart diseases ; Humans ; Hyperplasia - metabolism ; Hyperplasia - pathology ; Immune response ; Immune system ; Immunosuppressive agents ; Infant ; Lung - metabolism ; Lung diseases ; Lungs ; Metabolism ; Neonates ; Patients ; Pulmonary Alveoli - metabolism ; Pulmonary arteries ; Pulmonary artery ; Pulmonary Circulation ; Rats ; Signal transduction ; Swine ; Tetralogy of Fallot ; Vascularization ; Weight loss ; Wnt protein</subject><ispartof>American journal of physiology. Lung cellular and molecular physiology, 2023-02, Vol.324 (2), p.L89-L101</ispartof><rights>Copyright American Physiological Society Feb 2023</rights><rights>Copyright © 2023 The Authors. 2023 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-15f5ad0b0da11a8806f00587770b8b01ab30576485deff6580f6b89aa8cc7b03</citedby><cites>FETCH-LOGICAL-c430t-15f5ad0b0da11a8806f00587770b8b01ab30576485deff6580f6b89aa8cc7b03</cites><orcidid>0000-0002-1495-0942 ; 0000-0001-5182-4278 ; 0000-0001-5514-2899 ; 0000-0003-4691-3780 ; 0000-0001-8808-2810</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3039,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36472329$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, De-Bao</creatorcontrib><creatorcontrib>Xu, Xiu-Xia</creatorcontrib><creatorcontrib>Hu, Yu-Qing</creatorcontrib><creatorcontrib>Cui, Qing</creatorcontrib><creatorcontrib>Xiao, Ying-Ying</creatorcontrib><creatorcontrib>Sun, Si-Juan</creatorcontrib><creatorcontrib>Chen, Li-Jun</creatorcontrib><creatorcontrib>Ye, Lin-Cai</creatorcontrib><creatorcontrib>Sun, Qi</creatorcontrib><title>Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms</title><title>American journal of physiology. Lung cellular and molecular physiology</title><addtitle>Am J Physiol Lung Cell Mol Physiol</addtitle><description>Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of patients with CHD with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia.</description><subject>Alveoli</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Biological activity</subject><subject>Blood flow</subject><subject>Body weight</subject><subject>Body weight loss</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular diseases</subject><subject>Child</subject><subject>Congenital diseases</subject><subject>Cyanosis</subject><subject>Cyclosporins</subject><subject>Dysplasia</subject><subject>Flow cytometry</subject><subject>Gene sequencing</subject><subject>Heart Defects, Congenital - complications</subject><subject>Heart Defects, Congenital - metabolism</subject><subject>Heart Defects, Congenital - pathology</subject><subject>Heart diseases</subject><subject>Humans</subject><subject>Hyperplasia - metabolism</subject><subject>Hyperplasia - pathology</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunosuppressive agents</subject><subject>Infant</subject><subject>Lung - metabolism</subject><subject>Lung diseases</subject><subject>Lungs</subject><subject>Metabolism</subject><subject>Neonates</subject><subject>Patients</subject><subject>Pulmonary Alveoli - metabolism</subject><subject>Pulmonary arteries</subject><subject>Pulmonary artery</subject><subject>Pulmonary Circulation</subject><subject>Rats</subject><subject>Signal transduction</subject><subject>Swine</subject><subject>Tetralogy of Fallot</subject><subject>Vascularization</subject><subject>Weight loss</subject><subject>Wnt protein</subject><issn>1040-0605</issn><issn>1522-1504</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1r3DAQhkVpaNJt_0APxdBLL96MZOvDl0JZ-gWBXpKzGFvyrhZZciW7sP8-SrINbU8zMO-8vDMPIe8obCnl7BqPs1_DfgtAO75lwNgLclUGrKYc2pelhxZqEMAvyeucjwDAAcQrctmIVrKGdVfkbhfD3ga3oK8OFtNSGZctZltjznFwuFhTzaufYsB0qswpzx6zwwqDqdySqzUYm_zJhX012eGAweUpvyEXI_ps357rhtx-_XK7-17f_Pz2Y_f5ph7aBpYSc-RooAeDlKJSIMYSUUkpoVc9UOwb4FK0ihs7joIrGEWvOkQ1DLKHZkM-PdnOaz9ZM9iwJPR6Tm4qYXVEp_-dBHfQ-_hbdx3jVLTF4OPZIMVfq82LnlwerPcYbFyzZrL8SYquPGtDPvwnPcY1hXJdUUnaqJY3qqjYk2pIMedkx-cwFPQDNH2Gph-h6QdoZen932c8r_yh1NwDWxuWZg</recordid><startdate>20230201</startdate><enddate>20230201</enddate><creator>Li, De-Bao</creator><creator>Xu, Xiu-Xia</creator><creator>Hu, Yu-Qing</creator><creator>Cui, Qing</creator><creator>Xiao, Ying-Ying</creator><creator>Sun, Si-Juan</creator><creator>Chen, Li-Jun</creator><creator>Ye, Lin-Cai</creator><creator>Sun, Qi</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TS</scope><scope>7U7</scope><scope>C1K</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1495-0942</orcidid><orcidid>https://orcid.org/0000-0001-5182-4278</orcidid><orcidid>https://orcid.org/0000-0001-5514-2899</orcidid><orcidid>https://orcid.org/0000-0003-4691-3780</orcidid><orcidid>https://orcid.org/0000-0001-8808-2810</orcidid></search><sort><creationdate>20230201</creationdate><title>Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms</title><author>Li, De-Bao ; Xu, Xiu-Xia ; Hu, Yu-Qing ; Cui, Qing ; Xiao, Ying-Ying ; Sun, Si-Juan ; Chen, Li-Jun ; Ye, Lin-Cai ; Sun, Qi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-15f5ad0b0da11a8806f00587770b8b01ab30576485deff6580f6b89aa8cc7b03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Alveoli</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Biological activity</topic><topic>Blood flow</topic><topic>Body weight</topic><topic>Body weight loss</topic><topic>Cardiovascular disease</topic><topic>Cardiovascular diseases</topic><topic>Child</topic><topic>Congenital diseases</topic><topic>Cyanosis</topic><topic>Cyclosporins</topic><topic>Dysplasia</topic><topic>Flow cytometry</topic><topic>Gene sequencing</topic><topic>Heart Defects, Congenital - complications</topic><topic>Heart Defects, Congenital - metabolism</topic><topic>Heart Defects, Congenital - pathology</topic><topic>Heart diseases</topic><topic>Humans</topic><topic>Hyperplasia - metabolism</topic><topic>Hyperplasia - pathology</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Immunosuppressive agents</topic><topic>Infant</topic><topic>Lung - metabolism</topic><topic>Lung diseases</topic><topic>Lungs</topic><topic>Metabolism</topic><topic>Neonates</topic><topic>Patients</topic><topic>Pulmonary Alveoli - metabolism</topic><topic>Pulmonary arteries</topic><topic>Pulmonary artery</topic><topic>Pulmonary Circulation</topic><topic>Rats</topic><topic>Signal transduction</topic><topic>Swine</topic><topic>Tetralogy of Fallot</topic><topic>Vascularization</topic><topic>Weight loss</topic><topic>Wnt protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, De-Bao</creatorcontrib><creatorcontrib>Xu, Xiu-Xia</creatorcontrib><creatorcontrib>Hu, Yu-Qing</creatorcontrib><creatorcontrib>Cui, Qing</creatorcontrib><creatorcontrib>Xiao, Ying-Ying</creatorcontrib><creatorcontrib>Sun, Si-Juan</creatorcontrib><creatorcontrib>Chen, Li-Jun</creatorcontrib><creatorcontrib>Ye, Lin-Cai</creatorcontrib><creatorcontrib>Sun, Qi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Physical Education Index</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of physiology. Lung cellular and molecular physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, De-Bao</au><au>Xu, Xiu-Xia</au><au>Hu, Yu-Qing</au><au>Cui, Qing</au><au>Xiao, Ying-Ying</au><au>Sun, Si-Juan</au><au>Chen, Li-Jun</au><au>Ye, Lin-Cai</au><au>Sun, Qi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms</atitle><jtitle>American journal of physiology. Lung cellular and molecular physiology</jtitle><addtitle>Am J Physiol Lung Cell Mol Physiol</addtitle><date>2023-02-01</date><risdate>2023</risdate><volume>324</volume><issue>2</issue><spage>L89</spage><epage>L101</epage><pages>L89-L101</pages><issn>1040-0605</issn><eissn>1522-1504</eissn><abstract>Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of patients with CHD with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>36472329</pmid><doi>10.1152/ajplung.00195.2022</doi><orcidid>https://orcid.org/0000-0002-1495-0942</orcidid><orcidid>https://orcid.org/0000-0001-5182-4278</orcidid><orcidid>https://orcid.org/0000-0001-5514-2899</orcidid><orcidid>https://orcid.org/0000-0003-4691-3780</orcidid><orcidid>https://orcid.org/0000-0001-8808-2810</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Alveoli Animals Animals, Newborn Biological activity Blood flow Body weight Body weight loss Cardiovascular disease Cardiovascular diseases Child Congenital diseases Cyanosis Cyclosporins Dysplasia Flow cytometry Gene sequencing Heart Defects, Congenital - complications Heart Defects, Congenital - metabolism Heart Defects, Congenital - pathology Heart diseases Humans Hyperplasia - metabolism Hyperplasia - pathology Immune response Immune system Immunosuppressive agents Infant Lung - metabolism Lung diseases Lungs Metabolism Neonates Patients Pulmonary Alveoli - metabolism Pulmonary arteries Pulmonary artery Pulmonary Circulation Rats Signal transduction Swine Tetralogy of Fallot Vascularization Weight loss Wnt protein |
| title | Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms |
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