RESPIRATORY TRACT DEVELOPMENT

1. RESPIRATORY TRACT DEVELOPMENT Assist. Prof. Alev CUMBUL PhD. 07.11.2013

2. OBJECTIVES • Introduction • Primordium of Respiratory Tract • Development of the Larynx • Development of the Trachea • Development of the Bronchi and Lung • Maturation of the Lung

3. Introduction • The foregut can be divided into three parts: • The first part lies ventral to the developing brain, and forms the primitive pharynx, which has the branchial arches associated with it. • The second part lies dorsal to the heart, and forms the lung bud and the oesophagus. • The thirdpartlies dorsal to the septum transversum and forms the stomach and other related gastro- intestinal structures.

4. Introduction • The respiratory system is a derivative of the second part of the foregut. • It begins to develop in the beginning of the fourth week (day 22) • It begins as a laryngo- tracheal groove on the ventral aspect of the foregut, which deepens and forms a repiratory diverticulum. • Separates from the oesophagus

5. Introduction

6. Primordium of Respiratory Tract • The endoderm lining the laryngotracheal groove gives rise to bronchi and pulmonary epithelium. • By the end of fourth week, the laryngotracheal groove has evaginatedto form a pouch like laryngotrachealdiverticulum. • This diverticulum elongates and invested with splanchnic mesenchyme and its distal end enlarges to form a globular respiratory bud.

7. Primordium of Respiratory Tract • Laryngotrachealdiverticulum separated from the primitive pharynx (cranial part of the foregut) by longitudinal tracheoesophageal folds. • During the 4th and 5th weeks, these folds fuse and form the tracheoesophageal septum, which is a partition dividing the foregut into a ventral and a dorsal portion. • The ventral portion is the laryngotracheal tube that eventually becomes the larynx, trachea, bronchi, and lungs. • The dorsal portion becomes the esophagus.

9. Development of the Larynx • The epithelial lining of the larynx develops from endoderm of the cranial end of laryngotrachealtube • The cartilages of the larynx develop from the cartilages in the fourth and sixth pairs of pharyngeal arches • The laryngeal cartilages develop from the mesenchyme that is derived from neural crest cells • Intrinsic muscles of larynx (originate from occipital somites 1 and 2)

10. Development of the Larynx • The laryngeal epithelium proliferates rapidly resulting in temporary occlusion of the laryngeal lumen • Recanalization of larynx normally occurs by the tenth week • Laryngeal ventricles form during this recanalization • These recesses are bounded by folds of mucous membrane that become the vocal folds and vestibular folds

11. Development of the Larynx • The epiglottis develops from the caudal part of the hypopharyngeal eminence • The rostral part of this eminence forms the posterior third or pharyngeal part of the tongue • Growth of the larynx and epiglottis is rapid during the first three years after birth • By this time the epiglottis has reached its adult form

13. Development of the Trachea • The lung starts as an evagination, from the esophageal endoderm, called the larygotracheal groove • The endodermal lining of the laryngotracheal tube distal to the (larynx differentiates )into the epithelium and glands of the trachea and pulmonary epithelium • The cartilages, connective tissue, and muscles of the trachea are derived from the splanchnic mesenchyme surrounding the laryngotracheal tube

17. Tracheo-esophagal Septum • Partial cell death and tissue liquifaction normally occurs in this septumduring the 4th week, seperating the esophagus from the trachea. • Abnormal septal inhibition accounts for a variety of defects.

18. Tracheal Stenosis • The narrowing, brought about by ventral septal inhibition, is usually localized. • Respiratory distress is complicated by feeding difficulties in early neonatal life.

19. Tracheal Agenesis • If the lung buds are sparedi the bronchial tree develops normally. • The main bronchi, seperately or conjoined, communicate with the esophagus.

20. Esophageal Atresia • The tracheal bud is the site of rapid cell proliferation of the tracheal outgrowth from the second (oesophageal part of the fore gut. • This is followed by apoptosis to convert the outgrowth into a tubular structure.

21. Esophageal Atresia • At the same time, the second (oesophageal) part of the foregut also proliferates rapidly. • Then , lumen is re-canalization by apoptosis. • A defect in programming of foregut differentiation results in oesophagealatresia or tracheo-oesophageal atresia or both. • The oesophagus often communicates with the trachea either above or below the atresia.

22. Tracheo-oesophageal fistula • It is an abnormal passage between the trachea and esophagus • Occurs once in 3000 to 4500 live births • Most affected infants are males • In more than 85% of cases, the fistula is associated with esophageal atresia • It results from incomplete division of the cranial part of the foregut into respiratory and esophageal parts

23. Tracheo-oesophageal fistula • Theincidence of oesophagealatresia (OA) is approximately1 in 3000 to 4500 births • SYMPTOMS& SIGNS: • Polyhydramnios, • Excessive oral secretions • Chokingandregurgitationaccompanyfeeding • Leadingto aspiration pneumonia. • Abdominaldistension • Inabilitytointroduce a naso-gastrictube • X-raysoftenshowsabsence of a stomachbubble, but thismay be presentdepending on the site of theatresia. • Treatment is by surgery, usually after aperiod of feeding via gastrostomy.

24. Tracheo-oesophagealfistula Oesophageal Atresia with a proximal fistula. Oesophagealatresiacombinedwithfistulaefrombothoesophagealsegments. OesophagealAtresiawith a distaltracheo-oesophagealfistula. Isolated Oesophageal Atresia without a fistula. Tracheo-oesophageal fistula of the”N” or “H” type

26. LUNG DEVELOPMENT Therespiratorybudthatdeveloped at thecaudalend of thelaryngotrachealdiverticulumduringthefourthweek. Therespiratorydiverticulumbifurcatesintorightandleftbronchialbuds on day 26-28.

27. STAGE OF LUNG DEVELOPMENT Lungdevelopment is subdivided 6 periods: Embryonicperiod Pseudoglandularperiod Canalicularperiod Saccularperiod Alveolarperiod PostnatalLungGrowth

29. General Features: • Theconnection of eachbronchialbudwiththetracheaenlargesto form theprimordium of a main bronchus. • Thisperiodoccurs 3-6 weeks. • Characteristicchanges: • Twobronchi– rightandleft main andbranchingto form bronchi • Theprimitiveepithelialcellsare form at 4 weeks. Embryonic Phase

30. EmbryonicPhase Asymmetricbranchingoccursduringthefollowing 2 weeksto form secondarybronchi: 3 on therightand 2 on theleftformingthe main divisions of thebronchialtree.

31. EmbryonicPhase The lung bud and its subsequent branches are of endodermal origin. They give rise to the epitheliumlining all the respiratory passages, the alveoli and the associated glands. The surrounding mesoderm, the splanchnopleure, gives rise to all the supporting structures: the connective tissue, cartilage, muscle and blood vessels.

32. EmbryonicPhase Thepattern of branching is regulatedbythesurroundingmesoderm. Themesodermsurroundingthetracheainhibitsbranchingwhereasthemesodermsurroundingthebronchistimulatesbranching.

33. EmbryonicPhase Asymmetricbranching in week 5 formsthelobes of thelungs:

34. EmbryonicPhase Inweek 6 the 4th set of branchingformstertiarybronchiandthebroncho-pulmonarysegments

35. LUNG DEVELOPMENT • During weeks 7 to 16 branching occurs about 14 times to the level of terminal bronchioles • At thisstagetherearenoalveoli. • This period is described as the glandular stage because the terminal bronchioles resemble glandular acini.

36. Pseudoglandular (Glandular) Phase (Ps) General Features: Thebronchiaredividingintosmallerandsmallerunits, thebronchioles. Thisperiodoccursfromthe 2nd mounththroughtheend of the 4th month. Characteristicchanges: Bronchi is continuedairwaybranchingtoterminal bronchioles. Neurosecretorycellsfirstlyappear at 8 weeks Presecretoryandpreciliated at 10-12 weeks Ciliatedcells, neuroepithelialbodiesaredifferentiated at 14 weeks Smoothmuscle, cartilageandmucousglandsdevelops. Pleuralperitonealcavities is closed.

38. General Features: • Duringthenext 16 and 22 weekstherespiratorybronchiolesareformed. • Theywillgiverisetoalveolarductslatermonth. • Characteristicchanges: • Duringthis time periodtheepitheliumremains as a cuboidalepithelium • Surfactantbeginsto be producedfromsixmonths (24 Week). • Type II pneumocytessecrete a mixture of phospholipidscalledsurfactant • 20 – 22 weeks: pre-claracellstransformetoclaracell. • 24 weeks: Type I andType II • 24 – 26 weeks: claracells Canalicular Phase (Can)

40. General Features: • Thisphase of developmentoccursfromthe 26 weeksuntil 36 weeks. • At thesame time the terminal sacs form. • Characteristicchanges: • Terminal sacculesarelinedmainlybysquamousepithelialcells. ThesecellsType I alveolarcellswhich is developed at 26 weeks. • Theywillpermitgaseousexchange. • Duringthe 7th monththattype II alveolarepithelialcellsdevelop. • Thesetype II cellsproducesurfactant, thefluidthatreducesthesurfacetension at thealveolarcellsurface. • Hence, fromthe 7th month on thefetus is capable of survival Saccular Phase(Sac)

42. General Features: • Secondaryseptationstarts. • Duringthe 32 weeksand 3 years, thematurealveolicontinueto be formedwith an increase in theamount of surfaceareawherecapillariesandalveolarcellsare in contact. • Characteristicchanges: • Thegrowth of thelungsafterbirth is mainlytheresult of increases in thenumber of alveoliduringthis time. Alveolar Phase

43. Alveoliphase Alveolarduct Primaryseptum Alveolar sac Type I pneumocyte Type II pneumocyte Capillaries

44. Thephaseoccurs 3 yearstothen • Thealveolarformation is completedabout 85% . Postnatal Lung Growth

45. LUNG DEVELOPMENT • Surfactantbeginsto be producedfromsixmonths (24 Week) in utero. • Lungfluid is beingproduced at a rate of 300mls/day at term; • Thisfillsthelungstotheirrestingvolume of 100 mls. • Also, it is contributedtobytheswallowing of aminioticfluid; thismay be forciblyexhaled at birthorabsorbedintothelungs. • Thecombination of breathingmovementsandsufficientliquorvolumeaidproperlungdevelopment

46. RESPIRATORY CHANGES AT THE BIRTH • Thefollowschangesoccur at birth: • Lungliquid is reabsorbed - chestcompressionsqueezesout a third of thefluid, adrenalinpromotesreabsorption of the rest. • Surfactant is released, triggeredby adrenalin andsteroids. Synthesis is alsobegun. • A fall in thecapillarypressure of thelungsoccurswiththeexpansion of thealveoli, andthevasodilatoryeffect of oxygen. Othercirculatorychangestakeplace - physiologicalclosure of theductusarteriosusandforamen ovale, suchthatwhole of thecardiacoutputflowsvialungs • respiratorymovements of thechestcommence

47. RESPIRATORY CHANGES AT THE BIRTH • From third to eight year or so, the number of immature alveoli continues to increase • Unlike mature alveoli, immature alveoli have the potential for forming additional primordial alveoli • About 50 million alveoli, one sixth of the adult number are present in the lungs of a full-term newborn infant • By about the eighth year, the adult complement of 300 million alveoli is present

49. RESPIRATORY CHANGES AT THE BIRTH • By birth the fetus has had the advantage of breathing exercise for months • These movements stimulate lung development • At birth the lungs are half filled with fluid derived from the amniotic cavity, lungs and tracheal glands The fluid in the lungs is cleared at birth by three routes: • Through the mouth and nose by pressure on the fetal thorax during delivery • Into the pulmonary capillaries • Into the lymphatics and pulmonary arteries and veins