Respiratory System - Diaphragm: Difference between revisions

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== Introduction ==
== Introduction ==
[[File:Bailey298.jpg|thumb|Historic diagram showing the position of the diaphragm in human embryos of different stages.]]
[[File:Bailey298.jpg|thumb|Historic diagram showing the position of the diaphragm in human embryos of different stages.]]
[[File:Adult diaphragm.jpg|thumb|Adult Diaphragm]]
[[File:Gray0391.jpg|thumb|Adult Diaphragm]]
The respiratory system does not carry out its physiological function (gas exchange) prenatally and postnatally the lungs continue to grow for another 8+ years. Many other tissues/systems are involved in respiratory function: musculoskeletal (ribs and diaphragm) cardiovascular (pulmonary circulation). The musculoskeletal begins functioning prenatally, the cardiovasular pulmonary circulation is activated and altered postnatally.
The {{diaphragm}} is part of the {{musculoskeletal}} system, along with ribs and intercostals, that mechanically support respiration. In humans, the muscles of the diaphragm arise from somite level 3 to 5 (C3 to C5), which also corresponds to the levels of segmental nerves providing innervation of the diaphragm. The diaphragm begins functioning prenatally, and in the third trimester preparatory {{fetal respiratory movements}} occur, that are thought to have a number of roles in late respiratory and perhaps neural development.


The diaphragm along with the ribcage are the musculoskeletal structures that regulate lung inflation. The topic of musculoskeletal development is also covered in a separate set of notes (More? [[Musculoskeletal System Development]]).


In humans, the muscles of the diaphragm arise from somite level 3 to 5 (C3 to C5), which also corresponds to the levels of segmental nerves providing innervation of the diaphragm.
Failure of complete diaphragm development can lead to a herniation of abdominal components through channels or gaps in the developing diaphragm into the pleural cavity.


Failure of complete diaphragm development can lead to a herniation of abdominal components through channels or gaps in the developing diaphragm into the pleural cavity.


In humans, in the third trimester preparatory [[#Fetal_Respiratory_Movements|fetal respiratory movements]] occur, which are thought to have a number of roles in late respiratory development.


:{{Template:Respiratory Links}}
The respiratory system does not carry out its physiological function (gas exchange) prenatally and postnatally the lungs continue to grow for another 8+ years.  Respiration also is dependent upon the cardiovascular system, pulmonary circulation, developed prenatally activated and altered postnatally.
 
{{Respiratory Links}}
 
== Some Recent Findings ==
{|
|-bgcolor="F5FAFF"
|
* '''Ephrin-B1, -B2, and -B4 Expression is Decreased in Developing Diaphragms and Lungs of Fetal {{Rat}}s with Nitrofen-Induced Congenital Diaphragmatic Hernia'''{{#pmid:30469162|PMID30469162}} "Congenital diaphragmatic hernia (CDH) is assumed to originate from a malformation of the amuscular mesenchymal component of the primordial diaphragm. Mutations in ephrin-B1, a membrane protein that is expressed by mesenchymal cells, have been found in newborn infants with CDH and associated pulmonary hypoplasia (PH), highlighting its important role during diaphragmatic and airway development. Ephrin-B1, -B2, and -B4 are expressed in fetal rat lungs and have been identified as key players during lung branching morphogenesis. We hypothesized that diaphragmatic and pulmonary expression of ephrin-B1, -B2, and -B4 is decreased in the nitrofen-induced CDH model. Time-mated rats received nitrofen or vehicle on day 9 (D9). Fetal diaphragms (n = 72) and lungs (n = 72) were harvested on D13, D15, and D18, and divided into control and nitrofen-exposed specimens. Ephrin-B1, -B2, and -B4 gene expression was analyzed by quantitative real-time polymerase chain reaction. Immunofluorescence double staining for ephrin-B1, -B2, and -B4 was combined with mesenchymal and epithelial markers (Gata-4/Fgf-10 and calcitonin gene-related peptide) to evaluate protein expression/localization. ...Decreased ephrin-B1, -B2, and -B4 expression may disrupt diaphragmatic development and lung branching morphogenesis by interfering with epithelial-mesenchymal interactions, thus causing diaphragmatic defects and PH."
 
* '''Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle'''{{#pmid:29679560|PMID29679560}} "We find that the earliest developmental events are the emigration of muscle progenitors from cervical somites followed by the projection of phrenic nerve axons from the cervical neural tube. Muscle progenitors and phrenic nerve target the pleuroperitoneal folds (PPFs), transient pyramidal-shaped structures that form between the thoracic and abdominal cavities. Subsequently, the PPFs expand across the surface of the liver to give rise to the muscle connective tissue and central tendon, and the leading edge of their expansion precedes muscle morphogenesis, formation of the vascular network, and outgrowth and branching of the phrenic nerve. Thus development and morphogenesis of the PPFs is critical for diaphragm formation."
 
* '''Congenital diaphragmatic hernias: from genes to mechanisms to therapies'''{{#pmid:28768736|PMID28768736}} "Congenital diaphragmatic hernias (CDHs) and structural anomalies of the diaphragm are a common class of congenital birth defects that are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure. In ∼30% of CDH patients, genomic analyses have identified a range of genetic defects, including chromosomal anomalies, copy number variants and sequence variants. The affected genes identified in CDH patients include transcription factors, such as GATA4, ZFPM2, NR2F2 and WT1, and signaling pathway components, including members of the retinoic acid pathway. Mutations in these genes affect diaphragm development and can have pleiotropic effects on pulmonary and cardiac development. New therapies, including fetal endoscopic tracheal occlusion and prenatal transplacental fetal treatments, aim to normalize lung development and pulmonary vascular tone to prevent and treat lung hypoplasia and pulmonary hypertension, respectively."
|}
{| class="wikitable mw-collapsible mw-collapsed"
! More recent papers  
|-
| [[File:Mark_Hill.jpg|90px|left]] {{Most_Recent_Refs}}
 
Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Diaphragm+development ''Diaphragm development''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Fetal+respiratory+movements ''Fetal respiratory movements''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Phrenic+nerve+development ''Phrenic nerve development''] | [http://www.ncbi.nlm.nih.gov/pubmed/?term=Congenital+diaphragmatic+hernia ''Congenital diaphragmatic hernia'']
 
|}
{| class="wikitable mw-collapsible mw-collapsed"
! Older papers  
|-
| {{Older papers}}
* '''Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia'''{{#pmid:23650387|PMID23650387}} "Congenital diaphragmatic hernia (CDH) is a common birth defect that results in a high degree of neonatal morbidity and mortality, but its pathological mechanisms are largely unknown. ...We determined that RA signaling is necessary for the expression of tendon markers as well as the expression of other CDH-associated genes. Knockdown of Kif7, and retinoic acid receptors alpha (Rara), beta (Rarb), and gamma (Rarg) indicated that RA signaling is dependent on these genes to promote tendonogenesis within the embryonic diaphragm. Taken together, our results provide evidence for a model in which inhibition of RA receptor signaling promotes CDH pathogenesis through a complex gene network."
|}


== Diaphragm Components ==
== Diaphragm Components ==
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'''septum transversum '''- central tendon  
'''septum transversum '''- central tendon  


'''3rd to 5th somite''' - musculature of diaphragm (More? [skmus6.htm Somites])  
'''3rd to 5th somite''' - musculature of diaphragm (More? [[Somitogenesis]])  


'''ventral pleural sac''' - connective tissue  
'''ventral pleural sac''' - connective tissue  


'''mesentry of oesophagus''' - connective tissue around oesophasus and IVC (More? [git.htm Gastrointestinal Tract])  
'''mesentry of oesophagus''' - connective tissue around oesophasus and IVC (More? [[Gastrointestinal Tract Development]])  


'''pleuroperitoneal membranes''' - connective tissue around central tendon  
'''pleuroperitoneal membranes''' - connective tissue around central tendon  
|}
===Pleuroperitoneal Fold===
{|
| The transient '''pleuroperitoneal fold''' (PPF) arise from the posterior body wall, and appears in late week 4 ([[Carnegie stage 13|Carnegie stage 13]]/[[Carnegie stage 14|14]], CRL 6mm) and is present until week 6 ([[Carnegie stage 17|Carnegie stage 17]], CRL 14mm).{{#pmid:19711422|PMID19711422}} After this time it can no longer be separated from the diaphragm. These pair of folds have a triangular shape and abnormalities in their development is related to congenital diaphragmatic hernia (CDH).
| [[File:Bailey295.jpg|350px|alt=Rat pleuro-peritoneal membranes (historic drawing)]]


Rat pleuro-peritoneal membranes (historic drawing)
|}
|}


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The paired phrenic nerves are mixed containing motor neurons for the diaphragm and sensory nerves for other abdominal structures (mediastinum, pleura, liver, gall bladder).  
The paired phrenic nerves are mixed containing motor neurons for the diaphragm and sensory nerves for other abdominal structures (mediastinum, pleura, liver, gall bladder).  
The two adult phrenic nerves differ in their length, and also in their anatomical relations at the upper part of the thorax.


Netrin signaling may be important in early phrenic nerve growth, as knockout mice show incomplete phrenic nerve innervation of the diaphragm.
Netrin signaling may be important in early phrenic nerve growth, as knockout mice show incomplete phrenic nerve innervation of the diaphragm.
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Other respiratory muscles include the intercostals which are innervated by the intercostal nerves arising from segmental levels T1 to T11.
Other respiratory muscles include the intercostals which are innervated by the intercostal nerves arising from segmental levels T1 to T11.


'''References: '''
* Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period.{{#pmid:18403452|PMID18403452}}
 
* Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci.{{#pmid:16723533|PMID16723533}}
[http://www.ncbi.nlm.nih.gov/pubmed/18403452?dopt=Abstract Mantilla CB, Sieck GC.] Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period. J Appl Physiol. 2008 Jun;104(6):1818-27.
 
[http://www.ncbi.nlm.nih.gov/pubmed/16723533?dopt=Abstract Burgess RW, Jucius TJ, Ackerman SL.] Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci. J Neurosci. 2006 May 24;26(21):5756-66.


|}
|}
 
 
===Historic===
The images below are descending sections from a study of the 6 mm human embryo (~Carnegies stage {{CS14}}) phrenic nerve by Amin (1914).<ref name="Amin1914">{{Ref-Amin1914}}</ref>
<gallery>
File:Amin1914 fig01.jpg|level of fourth cervical ganglion
File:Amin1914 fig02.jpg|level of junction anterior cardinal vein with primitive subclavian vein from limb bud
File:Amin1914 fig03.jpg|level lateral to the duct of Cuvier
File:Amin1914 fig04.jpg|level early division of coelomic cavity
</gallery>


== Fetal Respiratory Movements ==
== Fetal Respiratory Movements ==
Fetal respiratory movements (FRM) or Fetal breathing movements (FBM) are thought to be regular muscular contrations occurring in the third trimester, preparing the respiratory muscular system for neonatal function and to have a role in late lung development.  
Fetal respiratory movements (FRM) or Fetal breathing movements (FBM) are thought to be regular muscular contrations occurring in the third trimester, preparing the respiratory muscular system for neonatal function and to also have a role in late lung development.  


The majority of FBM research has been carried out in fetal sheep.
The majority of FBM research has been carried out in fetal sheep.{{#pmid:8047386|PMID8047386}}


Hypoxia, decreased oxygen levels, blocks these movements by inhibition of the brain stem respiratory centres.  
Hypoxia, decreased oxygen levels, blocks these movements by inhibition of the brain stem respiratory centres.  
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Hormones also affect fetal breathing movements: inhibitors of prostaglandin synthetase (indomethacin, meclofenamate or aspirin) induce continuous fetal breathing movements, while prostaglandin E2 arrests fetal breathing.
Hormones also affect fetal breathing movements: inhibitors of prostaglandin synthetase (indomethacin, meclofenamate or aspirin) induce continuous fetal breathing movements, while prostaglandin E2 arrests fetal breathing.


'''References: '''
* The effect of fetal breathing movements on pulmonary blood flow in fetal sheep.{{#pmid:8047386|PMID8047386}} "FBM do not increase mean blood flow through the left pulmonary artery; thus, it is unlikely that FBM stimulate lung growth through changes in pulmonary blood flow."
* Maturation of fetal breathing activity.{{#pmid:8038281|PMID8038281}}
* The central control of fetal breathing and skeletal muscle movements.{{#pmid:6422029|PMID6422029}}
Hypercapnia (Greek, hyper = "above" and kapnos = "smoke") or hypercarbia increased carbon dioxide levels.


Savich RD, Guerra FA, Lee CC, Kitterman JA. The effect of fetal breathing movements on pulmonary blood flow in fetal sheep.Pediatr Res. 1994 Apr;35(4 Pt 1):484-9.<nowiki>PMID: 8047386 [PubMed - indexed for MEDLINE]</nowiki>
&nbsp;


"FBM do not increase mean blood flow through the left pulmonary artery; thus, it is unlikely that FBM stimulate lung growth through changes in pulmonary blood flow."
== Abnormalities ==
===LB00.0 Congenital Diaphragmatic Hernia===
[[File:Human_congenital_diaphragmatic_hernia.jpg|thumb|Human congenital diaphragmatic hernia{{#pmid:16483386|PMID16483386}}]]


Blanco CE. Maturation of fetal breathing activity.Biol Neonate. 1994;65(3-4):182-8. Review.<nowiki>PMID: 8038281 [PubMed - indexed for MEDLINE]</nowiki>
{|
|-bgcolor="FFCC00"
! {{ICD-11}}
|-bgcolor="FEF9E7"
|
{{ICD11weblink}}1139900219 LB00 Structural developmental anomalies of diaphragm]
* {{ICD11weblink}}1414428936 LB00.0 Congenital diaphragmatic hernia] - ''Congenital diaphragmatic hernia is a posterolateral defect of the diaphragm that allows passage of abdominal viscera into the thorax, leading to respiratory insufficiency and persistent pulmonary hypertension with high mortality.''
* {{ICD11weblink}}1952603717 LB00.1 Absence of diaphragm]
|}


Dawes GS. The central control of fetal breathing and skeletal muscle movements.J Physiol. 1984 Jan;346:1-18. Review.<nowiki>PMID: 6422029 [PubMed - indexed for MEDLINE]</nowiki>


Hypercapnia (Greek, hyper = "above" and kapnos = "smoke") or hypercarbia increased carbon dioxide levels.
Failure of the pleuroperitoneal foramen (foramen of Bochdalek) to close allows viscera into thorax. Intestine, stomach or spleen can enter the pleural cavity, compressing the lung. This can also be associated with abnormal lung development.{{#pmid:28641748|PMID28641748}}


&nbsp;
Bochdalek hernia - most common on the posterior left side (85%).


== Abnormalities ==
{|
'''Congenital Diaphragmatic Hernia''' (International Classification of Diseases code 756.6)
| [[File:Congenital_diaphragmatic_hernia_01.jpg|600px]]
|-
| Left posterolateral diaphragmatic hernia{{#pmid:22214468|PMID22214468}}


Failure of the pleuroperitoneal foramen (foramen of Bochdalek) to close allows viscera into thorax. Intestine, stomach or spleen can enter the pleural cavity, compressing the lung.
* '''A''' - Plain X-ray of the thorax of a newborn with CDH. There are bowel loops into the left hemi-thorax, the mediastinum is displaced to the contralateral side and the space occupied by the lung is reduced.  
 
* '''B''' - small bowel loops can be seen entering the thorax through the orifice.
Australian national rate (1982-1992) 2.1 - 3.8 /10,000 births. (Congenital Malformations Australia 1981-1992 P. Lancaster and E. Pedisich ISSN 1321-8352)
* '''C''' - seen after reducing the contents of the hernia.  
* '''D''' - At autopsy, extreme left lung hypoplasia and less severe right lung hypoplasia were discovered.
|}


'''References:'''  
Australian national rate (1982-1992) 2.1 - 3.8 /10,000 births.<ref>P. Lancaster and E. Pedisich '''Congenital Malformations Australia''' 1981-1992 ISSN 1321-8352.</ref>


[http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17177265&dopt=Abstract Gallot D, Boda C, Ughetto S, Perthus I, Robert-Gnansia E, Francannet C, Laurichesse-Delmas H, Jani J, Coste K, Deprest J, Labbe A, Sapin V, Lemery D.] Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study. Ultrasound Obstet Gynecol. 2007 Mar;29(3):276-83.  
* Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study.{{#pmid:17177265|PMID17177265}} "501 cases of CDH were identified from a total of 1,835,022 live births (2.7/10 000 live births). The overall prenatal detection rate was 54%."


"501 cases of CDH were identified from a total of 1,835,022 live births (2.7/10 000 live births). The overall prenatal detection rate was 54%."
* Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia.{{#pmid:16140678|PMID16140678}} "Ninety-two percent of postoperative infants survived beyond 1 year of age, as did 80% of infants who reached the surgical referral center. However, only 52% of live-born infants, 32% of all cases, and 16% of all prenatally diagnosed cases survived. Therefore, the overall mortality rate for this condition remains high, despite increased prenatal detection, transfer to tertiary institutions for delivery, and advances in neonatal care, and is influenced significantly by the rate of prenatal termination. In our study, 33% of all cases of CDH and 49% of prenatally diagnosed fetuses underwent elective termination of pregnancy. This large number of fetal terminations confounds the accurate assessment of the true outcomes of this condition."


[http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16140678&dopt=Abstract Colvin J, Bower C, Dickinson JE, Sokol J.] Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia. Pediatrics. 2005 Sep;116(3):e356-63.


"Ninety-two percent of postoperative infants survived beyond 1 year of age, as did 80% of infants who reached the surgical referral center. However, only 52% of live-born infants, 32% of all cases, and 16% of all prenatally diagnosed cases survived. Therefore, the overall mortality rate for this condition remains high, despite increased prenatal detection, transfer to tertiary institutions for delivery, and advances in neonatal care, and is influenced significantly by the rate of prenatal termination. In our study, 33% of all cases of CDH and 49% of prenatally diagnosed fetuses underwent elective termination of pregnancy. This large number of fetal terminations confounds the accurate assessment of the true outcomes of this condition."


'''Search Now:''' [http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=pubmed&cmd=search&doptcmdl=DocSum&term=congenital+diaphragmatic+hernia Pubmed - Congenital Diaphragmatic Hernia] | [http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=omim&cmd=search&doptcmdl=DocSum&term=congenital+diaphragmatic+hernia OMIM - Congenital Diaphragmatic Hernia]  
:'''Links:''' [[Respiratory_System_-_Abnormalities|Respiratory Abnormalities]] | [http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=pubmed&cmd=search&doptcmdl=DocSum&term=congenital+diaphragmatic+hernia Search Pubmed - CDH] | [http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=omim&cmd=search&doptcmdl=DocSum&term=congenital+diaphragmatic+hernia Search OMIM - CDH]


== Adult Diaphragm ==
== Adult Diaphragm ==
<center>[[Image:diaphragm.jpg]] </center>
<center>[[File:Gray0391.jpg]] </center>


<center>viewed from beneath</center>
<center>Historic image of adult diaphragm (viewed from beneath)</center>


== References ==
== References ==
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<references/>
<references/>
===Reviews===
===Reviews===
{{#pmid:29485899}}
{{#pmid:29679560}}


[http://www.ncbi.nlm.nih.gov/pubmed/18403452?dopt=Abstract Mantilla CB, Sieck GC.] Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period. J Appl Physiol. 2008 Jun;104(6):1818-27.
{{#pmid:22214468}}


[http://www.ncbi.nlm.nih.gov/pubmed/16723533?dopt=Abstract Burgess RW, Jucius TJ, Ackerman SL.] Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci. J Neurosci. 2006 May 24;26(21):5756-66.
{{#pmid:18510546}}
 
{{#pmid:18403452}}
 
{{#pmid:16723533}}


===Articles===
===Articles===
{{#pmid:26278035}}
{{#pmid:25807280}}
{{#pmid:21370493}}


===Search PubMed Now===
===Search PubMed Now===
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'''Search PubMed Now:''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=search&term=diaphragm%20development diaphragm development] | [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=search&term=phrenic%20nerve%20developmentm phrenic nerve development] | [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=search&term=fetal%20respiratory%20movements fetal respiratory movements] | [http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=pubmed&cmd=search&doptcmdl=DocSum&term=congenital+diaphragmatic+hernia Pubmed - Congenital Diaphragmatic Hernia] | [http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=omim&cmd=search&doptcmdl=DocSum&term=congenital+diaphragmatic+hernia OMIM - Congenital Diaphragmatic Hernia]  
'''Search PubMed Now:''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=search&term=diaphragm%20development diaphragm development] | [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=search&term=phrenic%20nerve%20developmentm phrenic nerve development] | [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=search&term=fetal%20respiratory%20movements fetal respiratory movements] | [http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=pubmed&cmd=search&doptcmdl=DocSum&term=congenital+diaphragmatic+hernia Pubmed - Congenital Diaphragmatic Hernia] | [http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=omim&cmd=search&doptcmdl=DocSum&term=congenital+diaphragmatic+hernia OMIM - Congenital Diaphragmatic Hernia]  


{{Template:Glossary}}


{{Template:Footer}}
 
 
{{Glossary}}
 
{{Footer}}
 
[[Category:Diaphragm]][[Category:Skeletal Muscle]][[Category:Respiratory]]

Latest revision as of 09:47, 17 April 2019

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Introduction

Historic diagram showing the position of the diaphragm in human embryos of different stages.
Adult Diaphragm

The diaphragm is part of the musculoskeletal system, along with ribs and intercostals, that mechanically support respiration. In humans, the muscles of the diaphragm arise from somite level 3 to 5 (C3 to C5), which also corresponds to the levels of segmental nerves providing innervation of the diaphragm. The diaphragm begins functioning prenatally, and in the third trimester preparatory fetal respiratory movements occur, that are thought to have a number of roles in late respiratory and perhaps neural development.


Failure of complete diaphragm development can lead to a herniation of abdominal components through channels or gaps in the developing diaphragm into the pleural cavity.


The respiratory system does not carry out its physiological function (gas exchange) prenatally and postnatally the lungs continue to grow for another 8+ years. Respiration also is dependent upon the cardiovascular system, pulmonary circulation, developed prenatally activated and altered postnatally.

Respiratory Links: respiratory | Science Lecture | Lecture Movie | Med Lecture | Stage 13 | Stage 22 | upper respiratory tract | diaphragm | Histology | Postnatal | respiratory abnormalities | Respiratory Quiz | Respiratory terms | Category:Respiratory
Historic Embryology - Respiratory 
1902 The Nasal Cavities and Olfactory Structures | 1906 Lung | 1912 Upper Respiratory Tract | 1912 Respiratory | 1913 Prenatal and Neonatal Lung | 1914 Phrenic Nerve | 1918 Respiratory images | 1921 Respiratory | 1922 Chick Pulmonary Vessels | 1934 Right Fetal Lung | 1936 Early Human Lung | 1937 Terminal Air Passages | 1938 Human Histology

Some Recent Findings

  • Ephrin-B1, -B2, and -B4 Expression is Decreased in Developing Diaphragms and Lungs of Fetal rats with Nitrofen-Induced Congenital Diaphragmatic Hernia[1] "Congenital diaphragmatic hernia (CDH) is assumed to originate from a malformation of the amuscular mesenchymal component of the primordial diaphragm. Mutations in ephrin-B1, a membrane protein that is expressed by mesenchymal cells, have been found in newborn infants with CDH and associated pulmonary hypoplasia (PH), highlighting its important role during diaphragmatic and airway development. Ephrin-B1, -B2, and -B4 are expressed in fetal rat lungs and have been identified as key players during lung branching morphogenesis. We hypothesized that diaphragmatic and pulmonary expression of ephrin-B1, -B2, and -B4 is decreased in the nitrofen-induced CDH model. Time-mated rats received nitrofen or vehicle on day 9 (D9). Fetal diaphragms (n = 72) and lungs (n = 72) were harvested on D13, D15, and D18, and divided into control and nitrofen-exposed specimens. Ephrin-B1, -B2, and -B4 gene expression was analyzed by quantitative real-time polymerase chain reaction. Immunofluorescence double staining for ephrin-B1, -B2, and -B4 was combined with mesenchymal and epithelial markers (Gata-4/Fgf-10 and calcitonin gene-related peptide) to evaluate protein expression/localization. ...Decreased ephrin-B1, -B2, and -B4 expression may disrupt diaphragmatic development and lung branching morphogenesis by interfering with epithelial-mesenchymal interactions, thus causing diaphragmatic defects and PH."
  • Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle[2] "We find that the earliest developmental events are the emigration of muscle progenitors from cervical somites followed by the projection of phrenic nerve axons from the cervical neural tube. Muscle progenitors and phrenic nerve target the pleuroperitoneal folds (PPFs), transient pyramidal-shaped structures that form between the thoracic and abdominal cavities. Subsequently, the PPFs expand across the surface of the liver to give rise to the muscle connective tissue and central tendon, and the leading edge of their expansion precedes muscle morphogenesis, formation of the vascular network, and outgrowth and branching of the phrenic nerve. Thus development and morphogenesis of the PPFs is critical for diaphragm formation."
  • Congenital diaphragmatic hernias: from genes to mechanisms to therapies[3] "Congenital diaphragmatic hernias (CDHs) and structural anomalies of the diaphragm are a common class of congenital birth defects that are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure. In ∼30% of CDH patients, genomic analyses have identified a range of genetic defects, including chromosomal anomalies, copy number variants and sequence variants. The affected genes identified in CDH patients include transcription factors, such as GATA4, ZFPM2, NR2F2 and WT1, and signaling pathway components, including members of the retinoic acid pathway. Mutations in these genes affect diaphragm development and can have pleiotropic effects on pulmonary and cardiac development. New therapies, including fetal endoscopic tracheal occlusion and prenatal transplacental fetal treatments, aim to normalize lung development and pulmonary vascular tone to prevent and treat lung hypoplasia and pulmonary hypertension, respectively."
More recent papers  
Mark Hill.jpg
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More? References | Discussion Page | Journal Searches | 2019 References | 2020 References

Search term: Diaphragm development | Fetal respiratory movements | Phrenic nerve development | Congenital diaphragmatic hernia

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia[4] "Congenital diaphragmatic hernia (CDH) is a common birth defect that results in a high degree of neonatal morbidity and mortality, but its pathological mechanisms are largely unknown. ...We determined that RA signaling is necessary for the expression of tendon markers as well as the expression of other CDH-associated genes. Knockdown of Kif7, and retinoic acid receptors alpha (Rara), beta (Rarb), and gamma (Rarg) indicated that RA signaling is dependent on these genes to promote tendonogenesis within the embryonic diaphragm. Taken together, our results provide evidence for a model in which inhibition of RA receptor signaling promotes CDH pathogenesis through a complex gene network."

Diaphragm Components

Diaphragm components.jpg Five elements contribute to the diaphragm.

septum transversum - central tendon

3rd to 5th somite - musculature of diaphragm (More? Somitogenesis)

ventral pleural sac - connective tissue

mesentry of oesophagus - connective tissue around oesophasus and IVC (More? Gastrointestinal Tract Development)

pleuroperitoneal membranes - connective tissue around central tendon

Pleuroperitoneal Fold

The transient pleuroperitoneal fold (PPF) arise from the posterior body wall, and appears in late week 4 (Carnegie stage 13/14, CRL 6mm) and is present until week 6 (Carnegie stage 17, CRL 14mm).[5] After this time it can no longer be separated from the diaphragm. These pair of folds have a triangular shape and abnormalities in their development is related to congenital diaphragmatic hernia (CDH). Rat pleuro-peritoneal membranes (historic drawing)

Rat pleuro-peritoneal membranes (historic drawing)

Diaphragm Innervation

Gray0804.jpg
Adult Cervical Plexus (phrenic nerve shown lower right)
Innervation of the human diaphragm is by the phrenic nerves, arising from the same segmental levels from which the diaphragm skeletal muscles arise, segmental levels C3 to C5.

The paired phrenic nerves are mixed containing motor neurons for the diaphragm and sensory nerves for other abdominal structures (mediastinum, pleura, liver, gall bladder).

The two adult phrenic nerves differ in their length, and also in their anatomical relations at the upper part of the thorax.

Netrin signaling may be important in early phrenic nerve growth, as knockout mice show incomplete phrenic nerve innervation of the diaphragm.

Other respiratory muscles include the intercostals which are innervated by the intercostal nerves arising from segmental levels T1 to T11.

  • Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period.[6]
  • Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci.[7]

 

Historic

The images below are descending sections from a study of the 6 mm human embryo (~Carnegies stage 14) phrenic nerve by Amin (1914).[8]

Fetal Respiratory Movements

Fetal respiratory movements (FRM) or Fetal breathing movements (FBM) are thought to be regular muscular contrations occurring in the third trimester, preparing the respiratory muscular system for neonatal function and to also have a role in late lung development.

The majority of FBM research has been carried out in fetal sheep.[9]

Hypoxia, decreased oxygen levels, blocks these movements by inhibition of the brain stem respiratory centres.

Hypercapnia, increased carbon dioxide levels, or acid cerebrospinal fluid perfusion can cause an increase in the regularity and depth of breathing.

Hormones also affect fetal breathing movements: inhibitors of prostaglandin synthetase (indomethacin, meclofenamate or aspirin) induce continuous fetal breathing movements, while prostaglandin E2 arrests fetal breathing.

  • The effect of fetal breathing movements on pulmonary blood flow in fetal sheep.[9] "FBM do not increase mean blood flow through the left pulmonary artery; thus, it is unlikely that FBM stimulate lung growth through changes in pulmonary blood flow."
  • Maturation of fetal breathing activity.[10]
  • The central control of fetal breathing and skeletal muscle movements.[11]

Hypercapnia (Greek, hyper = "above" and kapnos = "smoke") or hypercarbia increased carbon dioxide levels.

 

Abnormalities

LB00.0 Congenital Diaphragmatic Hernia

Human congenital diaphragmatic hernia[12]
 ICD-11

LB00 Structural developmental anomalies of diaphragm


Failure of the pleuroperitoneal foramen (foramen of Bochdalek) to close allows viscera into thorax. Intestine, stomach or spleen can enter the pleural cavity, compressing the lung. This can also be associated with abnormal lung development.[13]

Bochdalek hernia - most common on the posterior left side (85%).

Congenital diaphragmatic hernia 01.jpg
Left posterolateral diaphragmatic hernia[14]
  • A - Plain X-ray of the thorax of a newborn with CDH. There are bowel loops into the left hemi-thorax, the mediastinum is displaced to the contralateral side and the space occupied by the lung is reduced.
  • B - small bowel loops can be seen entering the thorax through the orifice.
  • C - seen after reducing the contents of the hernia.
  • D - At autopsy, extreme left lung hypoplasia and less severe right lung hypoplasia were discovered.

Australian national rate (1982-1992) 2.1 - 3.8 /10,000 births.[15]

  • Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study.[16] "501 cases of CDH were identified from a total of 1,835,022 live births (2.7/10 000 live births). The overall prenatal detection rate was 54%."
  • Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia.[17] "Ninety-two percent of postoperative infants survived beyond 1 year of age, as did 80% of infants who reached the surgical referral center. However, only 52% of live-born infants, 32% of all cases, and 16% of all prenatally diagnosed cases survived. Therefore, the overall mortality rate for this condition remains high, despite increased prenatal detection, transfer to tertiary institutions for delivery, and advances in neonatal care, and is influenced significantly by the rate of prenatal termination. In our study, 33% of all cases of CDH and 49% of prenatally diagnosed fetuses underwent elective termination of pregnancy. This large number of fetal terminations confounds the accurate assessment of the true outcomes of this condition."


Links: Respiratory Abnormalities | Search Pubmed - CDH | Search OMIM - CDH

Adult Diaphragm

Gray0391.jpg
Historic image of adult diaphragm (viewed from beneath)

References

  1. Takahashi T, Friedmacher F, Zimmer J & Puri P. (2019). Ephrin-B1, -B2, and -B4 Expression is Decreased in Developing Diaphragms and Lungs of Fetal Rats with Nitrofen-Induced Congenital Diaphragmatic Hernia. Eur J Pediatr Surg , 29, 113-119. PMID: 30469162 DOI.
  2. Sefton EM, Gallardo M & Kardon G. (2018). Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle. Dev. Biol. , , . PMID: 29679560 DOI.
  3. Kardon G, Ackerman KG, McCulley DJ, Shen Y, Wynn J, Shang L, Bogenschutz E, Sun X & Chung WK. (2017). Congenital diaphragmatic hernias: from genes to mechanisms to therapies. Dis Model Mech , 10, 955-970. PMID: 28768736 DOI.
  4. Coles GL & Ackerman KG. (2013). Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia. Proc. Natl. Acad. Sci. U.S.A. , 110, E1898-905. PMID: 23650387 DOI.
  5. Clugston RD, Zhang W & Greer JJ. (2010). Early development of the primordial mammalian diaphragm and cellular mechanisms of nitrofen-induced congenital diaphragmatic hernia. Birth Defects Res. Part A Clin. Mol. Teratol. , 88, 15-24. PMID: 19711422 DOI.
  6. Mantilla CB & Sieck GC. (2008). Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period. J. Appl. Physiol. , 104, 1818-27. PMID: 18403452 DOI.
  7. Burgess RW, Jucius TJ & Ackerman SL. (2006). Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci. J. Neurosci. , 26, 5756-66. PMID: 16723533 DOI.
  8. Amin M. The course of the phrenic nerve in the embryo. (1914) J Anat Physiol. 48(2): 215-8. PMID 17232992
  9. 9.0 9.1 Savich RD, Guerra FA, Lee CC & Kitterman JA. (1994). The effect of fetal breathing movements on pulmonary blood flow in fetal sheep. Pediatr. Res. , 35, 484-9. PMID: 8047386
  10. Blanco CE. (1994). Maturation of fetal breathing activity. Biol. Neonate , 65, 182-8. PMID: 8038281 DOI.
  11. Dawes GS. (1984). The central control of fetal breathing and skeletal muscle movements. J. Physiol. (Lond.) , 346, 1-18. PMID: 6422029
  12. Fisher JC & Bodenstein L. (2006). Computer simulation analysis of normal and abnormal development of the mammalian diaphragm. Theor Biol Med Model , 3, 9. PMID: 16483386 DOI.
  13. Ameis D, Khoshgoo N & Keijzer R. (2017). Abnormal lung development in congenital diaphragmatic hernia. Semin. Pediatr. Surg. , 26, 123-128. PMID: 28641748 DOI.
  14. Tovar JA. (2012). Congenital diaphragmatic hernia. Orphanet J Rare Dis , 7, 1. PMID: 22214468 DOI.
  15. P. Lancaster and E. Pedisich Congenital Malformations Australia 1981-1992 ISSN 1321-8352.
  16. Gallot D, Boda C, Ughetto S, Perthus I, Robert-Gnansia E, Francannet C, Laurichesse-Delmas H, Jani J, Coste K, Deprest J, Labbe A, Sapin V & Lemery D. (2007). Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study. Ultrasound Obstet Gynecol , 29, 276-83. PMID: 17177265 DOI.
  17. Colvin J, Bower C, Dickinson JE & Sokol J. (2005). Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia. Pediatrics , 116, e356-63. PMID: 16140678 DOI.

Reviews

Koo CW, Johnson TF, Gierada DS, White DB, Blackmon S, Matsumoto JM, Choe J, Allen MS, Levin DL & Kuzo RS. (2018). The breadth of the diaphragm: updates in embryogenesis and role of imaging. Br J Radiol , 91, 20170600. PMID: 29485899 DOI.

Sefton EM, Gallardo M & Kardon G. (2018). Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle. Dev. Biol. , , . PMID: 29679560 DOI.

Tovar JA. (2012). Congenital diaphragmatic hernia. Orphanet J Rare Dis , 7, 1. PMID: 22214468 DOI.

Pober BR. (2008). Genetic aspects of human congenital diaphragmatic hernia. Clin. Genet. , 74, 1-15. PMID: 18510546 DOI.

Mantilla CB & Sieck GC. (2008). Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period. J. Appl. Physiol. , 104, 1818-27. PMID: 18403452 DOI.

Burgess RW, Jucius TJ & Ackerman SL. (2006). Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci. J. Neurosci. , 26, 5756-66. PMID: 16723533 DOI.

Articles

Paris ND, Coles GL & Ackerman KG. (2015). Wt1 and β-catenin cooperatively regulate diaphragm development in the mouse. Dev. Biol. , 407, 40-56. PMID: 26278035 DOI.

Merrell AJ, Ellis BJ, Fox ZD, Lawson JA, Weiss JA & Kardon G. (2015). Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. Nat. Genet. , 47, 496-504. PMID: 25807280 DOI.

Hayashi S, Fukuzawa Y, Rodríguez-Vázquez JF, Cho BH, Verdugo-López S, Murakami G & Nakano T. (2011). Pleuroperitoneal canal closure and the fetal adrenal gland. Anat Rec (Hoboken) , 294, 633-44. PMID: 21370493 DOI.

Search PubMed Now

Search PubMed Now: diaphragm development | phrenic nerve development | fetal respiratory movements | Pubmed - Congenital Diaphragmatic Hernia | OMIM - Congenital Diaphragmatic Hernia



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Cite this page: Hill, M.A. (2024, March 28) Embryology Respiratory System - Diaphragm. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Respiratory_System_-_Diaphragm

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