{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T04:08:10Z","timestamp":1767586090985,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:00:00Z","timestamp":1613088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Congenital diaphragm hernia (CDH) is a congenital disease that occurs during prenatal development. Although the morbidity and mortality rate is rather significant, the pathogenesis of CDH has been studied insignificantly due to the decreased accessibility of human pathological material. Therefore the aim of our work was to evaluate growth factors (transforming growth factor-beta (TGF-\u03b2), basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), hepatocyte growth factor (HGF)) and their receptors (fibroblast growth factor receptor 1 (FGFR1), insulin-like growth factor 1 (IGF-1R)), muscle (dystrophin, myosin, alpha actin) and nerve quality (nerve growth factor (NGF), nerve growth factor receptor (NGFR), neurofilaments (NF)) factors, local defense factors (\u00df-defensin 2, \u00df-defensin 4), programmed cell death (TUNEL), and separate gene (Wnt-1) expression in human pathological material to find immunohistochemical marker differences between the control and the CDH patient groups. A semi-quantitative counting method was used for the evaluation of the tissues and structures in the Biotin-Streptavidin-stained slides. Various statistically significant differences were found in immunoreactive expression between the patient and the control group tissue and the morphological structures as well as very strong, strong, and moderate correlations between immunoreactives in different diaphragm cells and structures. These significant changes and various correlations indicate that multiple morphopathogenetic pathways are affected in CDH pathogenesis. This work contains the evaluation of the causes for these changes and their potential involvement in CDH pathogenesis.<\/jats:p>","DOI":"10.3390\/diagnostics11020289","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T18:45:00Z","timestamp":1613155500000},"page":"289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Morphofunctional Characterization of Different Tissue Factors in Congenital Diaphragmatic Hernia Affected Tissue"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7601-2847","authenticated-orcid":false,"given":"Ricards","family":"Kaulins","sequence":"first","affiliation":[{"name":"Institute of Anatomy and Anthropology, Riga Stradins University, 9 Kronvalda Boulevard, LV-1010 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1054-1997","authenticated-orcid":false,"given":"Laura Ramona","family":"Rozite","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Anthropology, Riga Stradins University, 9 Kronvalda Boulevard, LV-1010 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9804-4666","authenticated-orcid":false,"given":"Mara","family":"Pilmane","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Anthropology, Riga Stradins University, 9 Kronvalda Boulevard, LV-1010 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aigars","family":"Petersons","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Children\u2019s Clinical University Hospital, 45 Vienibas gatve Street, LV-1004 Riga, Latvia"},{"name":"Department of Pediatric Surgery, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"F137","DOI":"10.1136\/archdischild-2014-306174","article-title":"Epidemiology of congenital diaphragmatic hernia in Europe: A register-based study","volume":"100","author":"McGivern","year":"2015","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4026","DOI":"10.1111\/febs.12274","article-title":"Development of the diaphragm\u2014a skeletal muscle essential for mammalian respiration","volume":"280","author":"Merrell","year":"2013","journal-title":"Febs. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.jpedsurg.2014.08.005","article-title":"Congenital Diaphragmatic Hernia: Focus on Abnormal Muscle Formation","volume":"50","author":"Alaggio","year":"2015","journal-title":"J. Pediatric Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.siny.2014.09.003","article-title":"Genetic Causes of Congenital Diaphragmatic Hernia","volume":"19","author":"Wynn","year":"2014","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1292\/jvms.17-0193","article-title":"Early Development of Pleuroperitoneal Fold of the Diaphragm in the Rat Fetus","volume":"80","author":"Iwashita","year":"2018","journal-title":"J. Vet. Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/wdev.176","article-title":"The Fibroblast Growth Factor signaling pathway","volume":"4","author":"Ornitz","year":"2015","journal-title":"Wiley Interdiscip Rev. Dev. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"44735","DOI":"10.18632\/oncotarget.8203","article-title":"Molecular and clinical significance of fibroblast growth factor 2 (FGF2 \/bFGF) in malignancies of solid and hematological cancers for personalized therapies","volume":"7","author":"Akl","year":"2016","journal-title":"Oncotarget"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"16052","DOI":"10.18632\/oncotarget.14109","article-title":"Inhibition of the fibroblast growth factor receptor (FGFR) pathway: The current landscape and barriers to clinical application","volume":"8","author":"Chae","year":"2017","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6130","DOI":"10.1158\/1078-0432.CCR-11-0659","article-title":"Beyond VEGF: Inhibition of the Fibroblast Growth Factor Pathway and Antiangiogenesis","volume":"17","author":"Lieu","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/1479-5876-10-183","article-title":"TGF-\u03b2\u2014An Excellent Servant but a Bad Master","volume":"10","author":"Kubiczkova","year":"2012","journal-title":"J. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1016\/j.febslet.2012.05.010","article-title":"Post-translational regulation of TGF-\u03b2 receptor and Smad signaling","volume":"586","author":"Xu","year":"2012","journal-title":"Febs. Lett."},{"doi-asserted-by":"crossref","unstructured":"Hill, C.S. (2016). Transcriptional Control by the SMADs. Cold Spring Harb. Perspect Biol., 8.","key":"ref_12","DOI":"10.1101\/cshperspect.a022079"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.jdermsci.2017.08.003","article-title":"Cell-size-dependent upregulation of HGF expression in dermal fibroblasts: Impact on human skin connective tissue aging","volume":"88","author":"Qin","year":"2017","journal-title":"J. Derm. Sci."},{"doi-asserted-by":"crossref","unstructured":"Guerrero, P.A., and McCarty, J.H. (2017). TGF-\u03b2 Activation and Signaling in Angiogenesis. Physiol. Pathol. Angiogenesis Signal. Mech. Target. Ther.","key":"ref_14","DOI":"10.5772\/66405"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.ecl.2012.04.008","article-title":"Insulin-Like Growth Factor-1 Physiology: Lessons from Mouse Models","volume":"41","author":"Yakar","year":"2012","journal-title":"Endocrinol. Metab Clin. North. Am."},{"doi-asserted-by":"crossref","unstructured":"Fong, K.M., Larsen, J.E., Wright, C., Sriram, K., Davidson, M., Daniels, M., Sekido, Y., Bowman, R.V., Yang, I.A., and Minna, J.D. (2016). Molecular basis of lung carcinogenesis. Mol. Basis Hum. Cancer, 447\u2013496.","key":"ref_16","DOI":"10.1007\/978-1-59745-458-2_28"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.bcp.2017.12.009","article-title":"The interaction of IGF-1\/IGF-1R and hydrogen sulfide on the proliferation of mouse primary vascular smooth muscle cells","volume":"149","author":"Shuang","year":"2018","journal-title":"Biochem. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1161\/01.ATV.0000105902.89459.09","article-title":"Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels","volume":"24","author":"Delafontaine","year":"2004","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e12390","DOI":"10.1111\/cpr.12390","article-title":"IGF-1 Promotes Angiogenesis in Endothelial Cells\/Adipose-Derived Stem Cells Co-Culture System with Activation of PI3K\/Akt Signal Pathway","volume":"50","author":"Lin","year":"2017","journal-title":"Cell Prolif."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"301","DOI":"10.3390\/biomedicines2040301","article-title":"Hepatocyte Growth Factor Isoforms in Tissue Repair, Cancer, and Fibrotic Remodeling","volume":"2","author":"Mungunsukh","year":"2014","journal-title":"Biomedicines"},{"unstructured":"Kumar, V., Abbas, A.K., and Aster, J.C. (2014). The Cell as a Unit of Health and Disease. Robbins and Cotran Pathologic Basis of Disease, Elsevier. [9th ed.].","key":"ref_21"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1053\/j.sempedsurg.2017.04.011","article-title":"Abnormal lung development in congenital diaphragmatic hernia","volume":"26","author":"Ameis","year":"2017","journal-title":"Semin. Pediatr. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/imm.12717","article-title":"Nerve growth factor: A neuroimmune crosstalk mediator for all seasons","volume":"151","author":"Skaper","year":"2017","journal-title":"Immunology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1523\/JNEUROSCI.12-03-00930.1992","article-title":"Spatiotemporal patterns of expression of NGF and the low-affinity NGF receptor in rat embryos suggest functional roles in tissue morphogenesis and myogenesis","volume":"12","author":"Wheeler","year":"1992","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1111\/j.1460-9568.1993.tb00513.x","article-title":"The neurotrophins BDNF, NT-3 and NT-4\/5, but not NGF, up-regulate the cholinergic phenotype of developing motor neurons","volume":"5","author":"Wong","year":"1993","journal-title":"Eur. J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.mcn.2006.11.005","article-title":"Pro-NGF secreted by astrocytes promotes motor neuron cell death","volume":"34","author":"Domeniconi","year":"2007","journal-title":"Mol. Cell Neurosci."},{"key":"ref_27","first-page":"620","article-title":"Neurofilament proteins in axonal regeneration and neurodegenerative diseases","volume":"7","author":"Wang","year":"2012","journal-title":"Neural Regen Res."},{"unstructured":"Tang, Y.-W., Sussman, M., Liu, D., Poxton, I., and Schwartzman, J. (2015). Chapter 30\u2014Mammalian Antimicrobial Peptides; Defensins and Cathelicidins. Molecular Medical Microbiology, Academic Press. [2nd ed.].","key":"ref_28"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.peptides.2008.11.001","article-title":"Antimicrobial Human Beta-Defensin-2 Stimulates Migration, Proliferation and Tube Formation of Human Umbilical Vein Endothelial Cells","volume":"30","author":"Baroni","year":"2009","journal-title":"Peptides"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1096\/fj.00-0865fje","article-title":"Human \u03b2-defensin 4: A novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity","volume":"15","author":"Krause","year":"2001","journal-title":"Faseb J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0076-6879(07)28013-9","article-title":"Osmotic stress and DNA damage","volume":"428","author":"Ni","year":"2007","journal-title":"Methods Enzym."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/bdra.20613","article-title":"Early development of the primordial mammalian diaphragm and cellular mechanisms of nitrofen-induced congenital diaphragmatic hernia","volume":"88","author":"Clugston","year":"2010","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"unstructured":"Mudri, M. (2018). The Effects of Tracheal Occlusion on Wnt Signaling in a Rabbit Model of Congenital Diaphragmatic Hernia. Electron. Thesis Diss. Repos., Available online: https:\/\/ir.lib.uwo.ca\/etd\/5736.","key":"ref_33"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ydbio.2015.08.009","article-title":"Wt1 and \u03b2-Catenin Cooperatively Regulate Diaphragm Development in the Mouse","volume":"407","author":"Paris","year":"2015","journal-title":"Dev. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1749-6632.1998.tb10720.x","article-title":"Distribution of Galanin Immunoreactivity in the Bronchi of Humans with Tuberculosis","volume":"863","author":"Pilmane","year":"1998","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1073\/pnas.1121621109","article-title":"Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes","volume":"109","author":"Russell","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E38","DOI":"10.1161\/01.RES.88.4.e38","article-title":"Retinoids induce fibroblast growth factor-2 production in endothelial cells via retinoic acid receptor alpha activation and stimulate angiogenesis in vitro and in vivo","volume":"88","author":"Gaetano","year":"2001","journal-title":"Circ Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1093\/jn\/131.4.1189","article-title":"Vitamin A deficiency reduces insulin-like growth factor (IGF)-I gene expression and increases IGF-I receptor and insulin receptor gene expression in tissues of Japanese quail (Coturnix coturnix japonica)","volume":"131","author":"Fu","year":"2001","journal-title":"J. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7463","DOI":"10.3748\/wjg.v12.i46.7463","article-title":"Apoptosis in skeletal muscle and its relevance to atrophy","volume":"12","year":"2006","journal-title":"World J. Gastroenterol"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1080\/07853890701326883","article-title":"Molecular genetics of congenital diaphragmatic defects","volume":"39","author":"Bielinska","year":"2007","journal-title":"Ann. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/ijc.10166","article-title":"Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of the PI3K-Akt signaling pathway","volume":"98","author":"Nakashio","year":"2002","journal-title":"Int. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1002\/jcb.21265","article-title":"FGFR1\/PI3K\/AKT signaling pathway is a novel target for antiangiogenic effects of the cancer drug fumagillin (TNP-470)","volume":"101","author":"Chen","year":"2007","journal-title":"J. Cell Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1161\/01.RES.0000156273.30274.f7","article-title":"Walsh Kenneth Glycogen-Synthase Kinase3\u03b2\/\u03b2-Catenin Axis Promotes Angiogenesis Through Activation of Vascular Endothelial Growth Factor Signaling in Endothelial Cells","volume":"96","author":"Carsten","year":"2005","journal-title":"Circ. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1002\/ajmg.a.35665","article-title":"Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks","volume":"158A","author":"Longoni","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.tjog.2015.10.023","article-title":"Prenatal diagnosis of chromosome 8p23.1 microdeletion by array comparative genomic hybridization using uncultured amniocytes in a pregnancy associated with fetal partial corpus callosum agenesis and schizencephaly","volume":"54","author":"Chen","year":"2015","journal-title":"Taiwan J. Obs. Gynecol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0022-3468(95)90589-8","article-title":"Embryonic cell death patterns associated with nitrofen-induced congenital diaphragmatic hernia","volume":"30","author":"Alles","year":"1995","journal-title":"J. Pediatr. Surg."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.ydbio.2006.09.050","article-title":"Impaired mesenchymal cell function in Gata4 mutant mice leads to diaphragmatic hernias and primary lung defects","volume":"301","author":"Jay","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1742-4682-3-9","article-title":"Computer simulation analysis of normal and abnormal development of the mammalian diaphragm","volume":"3","author":"Fisher","year":"2006","journal-title":"Biol. Med. Model."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"337","DOI":"10.4161\/cam.3.4.9338","article-title":"Role of matrix metalloproteinases in skeletal muscle","volume":"3","author":"Chen","year":"2009","journal-title":"Cell Adh Migr"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11793","DOI":"10.1074\/jbc.M110.100479","article-title":"Nerve Growth Factor Inhibits Metalloproteinase-Disintegrins and Blocks Ectodomain Shedding of Platelet Glycoprotein VI","volume":"285","author":"Wijeyewickrema","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"30485","DOI":"10.1074\/jbc.M701081200","article-title":"Nerve growth factor induces endothelial cell invasion and cord formation by promoting matrix metalloproteinase-2 expression through the phosphatidylinositol 3-kinase\/Akt signaling pathway and AP-2 transcription factor","volume":"282","author":"Park","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"313","DOI":"10.4103\/0366-6999.174496","article-title":"Nerve Growth Factor Promotes Angiogenesis and Skeletal Muscle Fiber Remodeling in a Murine Model of Hindlimb Ischemia","volume":"129","author":"Diao","year":"2016","journal-title":"Chin. Med. J. (Engl.)"},{"doi-asserted-by":"crossref","unstructured":"Micera, A., Puxeddu, I., Balzamino, B.O., Bonini, S., and Levi-Schaffer, F. (2012). Chronic Nerve Growth Factor Exposure Increases Apoptosis in a Model of In Vitro Induced Conjunctival Myofibroblasts. PLoS ONE, 7.","key":"ref_53","DOI":"10.1371\/journal.pone.0047316"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/bs.pmbts.2016.09.010","article-title":"Wnt\/\u03b2 Catenin-Mediated Signaling Commonly Altered in Colorectal Cancer","volume":"144","author":"Deitrick","year":"2016","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1074\/jbc.M504875200","article-title":"The Wnt-inducible transcription factor Twist1 inhibits chondrogenesis","volume":"281","author":"Reinhold","year":"2006","journal-title":"J. Biol. Chem."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/11\/2\/289\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:23:23Z","timestamp":1760160203000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/11\/2\/289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,12]]},"references-count":55,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["diagnostics11020289"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics11020289","relation":{},"ISSN":["2075-4418"],"issn-type":[{"type":"electronic","value":"2075-4418"}],"subject":[],"published":{"date-parts":[[2021,2,12]]}}}