Organogenesis 3 - The Respiratory System PDF

We talk of the the respiratory system in continuum with the pharyngeal apparatus because it is a sort of evolution of it. Animals developed a diverticulum that was kept dry so that they could use gills in water and lungs on earth. The respiratory diverticulum develops from the foregut and it was ini...

We talk of the the respiratory system in continuum with the pharyngeal apparatus because it is a sort of evolution of it. Animals developed a diverticulum that was kept dry so that they could use gills in water and lungs on earth. The respiratory diverticulum develops from the foregut and it was initially a sort of sack where air was stored with very thin walls that allowed the oxygen to diffuse into capillaries. This diverticulum had then to be protected from water and separated from the digestive system —> this was solved by a sphincteric device: the larynx (which then developed as an organ for sound production). Until birth the placenta is responsible for gas exchange, after birth the lungs are The respiratory system is one of the most important systems for survival. FUNCTIONS OF THE RESPIRATORY SYSTEM: Air conduction —> passageway for air from the outside to the site of gas exchange Air filtration —> the epithelium lining the system filters air from dangerous organisms Gas exchange —> oxygen and carbon dioxide Production of sounds —> larynx Detection of substances in air (odorants, sense of smell) —> at the level of the roof our nasal cavity we have the olfactory epithelium Immune response associated to inhaled antigens —> the respiratory system is very exposed so it is an immunologically protected site The respiratory system is divided in TWO PORTIONS: CONDUCTING PORTION —> divided in two sites: 1. Passageways external to the lung (not enveloped in the lungs parenchyma: nasal cavities, pharynx, larynx, trachea and main bronchi) 2. Passageways inside the lungs (enveloped by the lungs parenchyma, bronchial tree up to the level of the terminal bronchioles) RESPIRATORY PORTION —> small saccular structures that allow the exchange of gases between blood and air (respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli) DEVELOPMENT OF THE LOWER RESPIRATORY SYSTEM (trachea, bronchial tree, alveoli) We are in the foregut portion of the intestinal tube and at the level of the primordial pharynx (where the oesophagus will develop). Here an endodermal diverticulum will form: respiratory bud or respiratory diverticulum or laryngotracheal diverticulum. The communication between the respiratory system and the digestive system is kept in the adult (if we close our nose we can still breath form the mouth). The communication between the digestive and respiratory system is at the level of the oropharynx (which is why we need a protective device to prevent food from going in the airways —> larynx). When we swallow the larynx acts as a sphincter. When babies are being breastfed they can still breath —> in babies the larynx is higher than in adults so that they can swallow and breath at the same time (because breastfeeding takes hours). The respiratory diverticulum develops around the 28th day of gestation from the floor of the primordial pharynx (a groove forms: laryngotracheal groove). It is an endodermal diverticulum. When the respiratory diverticulum starts to expands it expands in the mesenchyme of the dorsal mesocardium (dorsal to the heart). When the diverticulum expands it is not just endoderm anymore but it is endoderm + mesenchyme of the dorsal mesocardium (mesoderm). This means that the endodermal diverticulum is surrounded by splanchinc mesenchyme. Endoderm —> epithelial lining and glands Mesenchyme —> smooth muscle, cartilages, vessels In the beginning the lungs and the heart share the same cavity —> pleuropericardial cavity.  As the lungs grow they expand in the pericardial-peritoneal canals (connection between the pericardial cavity and peritoneal cavity) which will then become the future pleural cavities thanks to the formation of the pleuropericardial folds (they separate the pleural and pericardial cavities). The respiratory diverticulum develops caudal to the 4thweek primordial pharynx and in front of the oesophagus thanks to a specific molecular pattern. During this process a septum is created (the only communication with the gut tube has to be at the level of the oropharynx, where the communication is controlled). The process of separation between the respiratory bud TETEsue and gut tube has to be very precise. The tracheoesophageal septum gradually separates the growing respiratory diverticulum from the oesophagus The upper part of the respiratory diverticulum will give rise to the primitive trachea and larynx (only the larynx’ CT and smooth muscle, the cartilages originate from the 4th and 6th pharyngeal arches) The lower part of the respiratory diverticulum will give rise to the bronchial buds COMMUNICATION BETWEEN THE RESPIRATORY AND DIGESTIVE SYSTEM The communication is at the level of oropharynx. What we swallow goes into the hypopharynx (and then oesophagus) while air enters into the laryngeal inlet. The larynx doesn’t originate with the purpose of sound production but rather that of control (it acts as a sphincter). The laryngeal inlet originates from the opening of the initial slit (laryngotracheal groove), then the cartilages of the larynx arising from the 4th and 6th arches start to organise around the laryngotracheal groove changing its shape (it becomes T shaped) and leading to the formation of the laryngeal inlet. STRUCTURE OF THE LARYNX The cartilages of the larynx are divided into single and paired. The single ones are the cricoid and thyroid, while the paired are the arytenoids, the corniculates, the cuneiforms and the tritiates. The wall of the trachea is also formed by ligaments, which complete the parts made by cartilage. They can be intrinsic and extrinsic, broad and narrow, thick and thin and true and false vocal cords. The larynx is highly mobile in the neck. It can be moved up and down, forward and backward by the action of extrinsic muscles, which are attached either to the larynx itself or to the hyoid bone. During swallowing, the dramatic upward and forward movement of the larynx facilitate closing the laryngeal inlet and opening of the oesophagus. The diameter of the larynx is around 44 mm in males and around 36 mm in females. hypered cartilage et TRACHEA Caudal to the larynx the diverticulum differentiates into the trachea. The trachea is mostly cartilage and muscles (protection of the airway but also motility of the neck). The trachea is made of 16 to 20 C-shaped cartilages rings connected by annular ligaments TRACHEOESOPHAGEAL FISTULA —> anomalous communication between the trachea and the oesophagus. It is usually associated to oesophageal atresia or stenosis and often causes polyhydramnions. 2 CLINICAL PRESENTATION OF TRACHEOESOPHAGEAL FISTULA (TEF) In cases with oesophageal atresia, polyhydramnios occurs in approximately in 2/3 of pregnancies. Infants with oesophageal atresia become symptomatic immediately after birth, with excessive secretions resulting in drooling of saliva (can’t swallow correctly), choking, respiratory distress, and the inability to feed. After birth fluids can be diverted into the newly expanded lungs (causing pneumonia ab ingestis, inflammation). There might be choking and/or regurgitation of milk. Gagging and cyanosis might present after swallowing milk and there might be gastric reflux in the lungs. Tracheoesophageal fistula is usually associated to other defects such as cardiac, genitourinary or complex syndromes (VACTERL) BE sociatedalso might toproblemsinthenervous systemthatimply theinability controllingthemuscles ofthelarynxandsothedirectioning of offoodand air  Other less common defects: LARYNGOTRACHEOESOPHAGEAL CLEFT —> big cleft that keeps the larynx and the trachea in communication with the oesophagus (sagittal and posterior) TRACHEAL STENOSIS OR ATRESIA —> partial or total occlusion TRACHEAL DIVERTICULUM (or tracheal bronchus) —> the trachea might give rise to an extroflection that terminates into a normal appearing lung tissue (usually not functioning) that might give rise to respiratory infections and distress in infants (can store secretions that might spill in the tracheobronchial tree). DEVELOPMENT OF THE BRONCHIAL TREE At the end of the 4th week two PRIMARY BRONCHIAL BUDS will originate from the respiratory bud (endoderm inside, mesenchyme outside). 4thweek 11 opening onweek L Eighthe zegythe lift 5thweek bes robes broma brown tension rightprimarybronchus bronchi 3eobarbrouchim.tosegmental b Tachedeejiprimarybroncnit.ieaanbnonai8 woman Egmentee sits.frg IEsflessts BRONCHOPULMONARY SEGMENT —> it is the largest subdivision of a lobe and it is a region of large parenchyma with a triangular shape (apex towards lung root and base at pleural surface). Each segment is separated from the other by septa of connective tissue and each segment is supplied independently by a segmental branch of the bronchial artery and a tertiary branch of the pulmonary artery (poorly oxygenated blood). The segments are named according to the segmental bronchi suppling them and are drained by intersegmental pulmonary veins (oxygenated blood). These blocks are SURGICALLY RESECTABLE (as they’re independent from one another) segmental At the 24th weeks there will be another 17 orders of ramification and respiratory bronchioles and then 7 more after birth. The branching stabilises at the age of 8 years old. Branching is determined by the interaction between the endoderm and the surrounding mesoderm. Around the tracheal bud the mesoderm is inhibitory while around the bronchial buds the mesoderm promotes branching The crosstalk around the endoderm and mesenchyme allows the growing/stopping of growth of the diverticulum EEE's Green = tracheal epithelium Red = mesenchyme of bronchial buds (distal mesenchyme) 58 deeteuchyme FGF10 promotes branching, very important! If the endodermal sac stays without mesenchyme it doesn’t branch. If mesenchyme from the stomach is added then glands of the stomach mucosa will be formed. If mesenchyme from the intestine is added there will be the formation of villi and folds. If mesenchyme of the liver is added the bud starts to reproduce the hepatic cords. If the bronchial mesenchyme is added the sac tries to branch. If the tracheal mesenchyme is added nothing happens MATURATION OF THE LUNGS PARENCHYMA The maturation of the lungs parenchyma happens through stages and proceeds from proximal to distal, from apex to base and from largest bronchi to outwards. 4 STAGES OF MATURATION + embryonic stage (not really considered a stage): Embryonic stage —> from 26th day to 6th week, up to the segmental bronchi Pseudoglandular stage —> it looks very much like a gland in this stage —> 6th week to 16th week Canalicular stage —> from 16th week to 24-28th week Terminal sac stage —> from 24t-28th week to late fetal period Alveolar stage —> 32-36th week to 8 years old According to some authors true alveoli only mature after birth while according to some others they originate during fetal life, so there is an overlapping of the stages Purpose of lung maturation —> we have to reach the formation of a gas exchange barrier (otherwise survival isn’t possible) —> the GAS EXCHANGE BARRIER is made of very thin-walled air-containing sacs in contact with very thin-walled vessels (capillaries). Another essential event that needs to take place is the production of a substance called SURFACTANT that is able to reduce the surface tension of the alveoli. If there was no surfactant it would require an incredible effort for the gas exchange to happen + the alveoli would collapse during exhalation (atelectasis) PSEUDOGLANDULAR STAGE (6 to 16 week) The parenchyma is similar to an exocrine gland —> the endodermal tube is lined by simple columnar epithelium and surrounded by mesoderm with a modest capillary network. Each tube gives rise to additional branching up to terminal bronchioles. Here there is NO exchange possible and so NO survival (the tube stops at the level of the terminal bronchioles) CANALICULAR STAGE (16 to 24-28 week) Some respiratory bronchioles start arising from terminal bronchioles (first part of the respiratory portion). The respiratory bronchioles start to give rise to primordial alveolar ducts and terminal sacs (or primordial alveoli). The lining of the walls starts becoming a bit thinner while more capillaries arise close to the primordial alveoli. During the canalicular stage surfactant starts being produced (during 20th to 22nd week just a very little amount, a good amount starts to be found at the beginning of the 24th week of gestation). At this stage survival is possible but only with intensive care  SACCULAR STAGE (terminal sac stage 24th-28th to late fetal period) Alveolar ducts become more and more (with associated primordial alveoli). They’re called primordial alveoli and not just alveoli because development goes on until 8th year. The walls become even thinner and capillaries increase, bulging into the walls of the primary alveoli and creating the blood- air barrier. Primary septa (mesenchymal structures, pretty thick) start to divide the primordial alveoli. An important step of maturation is the deposition of elastic fibers in the septa that separates one alveoli from the other. Elastic fibers are very important because they create the elastic recoil during exhalation, which allows it to be a passive movement. The walls of the canaliculi are made of two types of flattened epithelia cells (type I pneumocytes, squamous epithelia lining the alveoli, and type II pneumocytes, surfactant producers). By the 24-28th week the foetus weights around 1kg and surfactant is enough for survival (with intensive care) ALVEOLAR STAGE (34-36th week until 8th year of age) The terminal sacs (primordial alveoli) start to be separated into smaller compartments (primary septa gives rise to protrusion —> secondary septa). The result is sacs similar to alveoli (not yet alveoli). Type I pneumocytes become thinner and the capillaries bulge in the lumen of alveoli. 95% of mature alveoli will form only after birth. At birth there are 20-70 million alveoli while after birth the number keeps increasing (300-400 million at 8 years old) BIautfaketh.is Titivalrespigjia.iqis kinthkfn99ak8iw PRIMARY SEPTA —> double layer of capillaries, thicker SECONDARY SEPTA —> single layer of capillaries, the primary septa is divided into smaller compartments while increasing in size. Secondary septa originate from primary septa MORPHO-FUNCTIONAL CONSIDERATION ON LUNG DEVELOPMENT : The lungs must be able to take charge of respiration after birth To perform post natal breathing the lungs have to be of an appropriate size, respiratory movement must occur continuously and the air sacs must configure for gas exchange Fetal breathing movement (since 10th week) —> the foetus has to practice his breathing by expanding and constricting the lungs during fetal life (helps maturation of respiratory system, trains the respiratory muscles and help with absorption of amniotic fluid). Fetal breathing is periodic (few times a day) and it is associated to REM sleep and connected to mother conditions (what affects mother might reflect on the foetus, if the mother smokes fetal breathing movement is decreased and excessive connective tissue is deposited in the septa of alveoli). At the moment of birth many things have to happen to free the respiratory system from fluids —> compression of the thoracic cavity along the birth canal, the nervous system has to be able to drive the muscles for breathing, baby crying (means that fluids are being expelled and nervous system is taking charge). The capillaries and lymphatic system re absorb excess fluid If the baby doesn’t take the first breath then the emptying process is not performed (lungs remain filled with fluids and don’t move). Lungs of stillborn babies sink in water (heavy because they’re full) WHEN THING GO WRONG RESPIRATORY DISTRESS SYNDROME (RDS) or hyaline membrane disease: It affects 2% of newborns —> premature infants and infants of diabetic mothers (the maturation of the parenchyma isn’t efficient enough) are much more susceptible. It is characterised by deficiency or absence of surfactant (if an infant is premature type II pneumocytes might not be working enough yet). The baby becomes cyanotic (more deoxygenated haemoglobin than oxygenated), he is in a respiratory distress (problems in breathing: gasping, tachypnea (accelerated breathing), dyspnea (shortness of breath, the baby is hungry for air), retraction for chest wall, nasal flaring) Treatment —> mechanical ventilation —> this damages the alveolar wall (too much stress) and so the walls start to be filled with the debris of cells (a glassy membrane called hyaline membrane forms, hence the alternative name) Another treatment (to induce the production of surfactant/increase the amount) —> corticosteroids given to the mother during pregnancy (trigger the maturation of the alveolar walls) or administering exogenous surfactant to the baby. GERMINAL MATRIX HAEMORRHAGE (GMS, brain bleeding: stroke in premature children) is usually associated to RDS. The brain is very sensitive to blood pressure changes but it has a system to protect it from excessive changes, however, in premature babies this mechanism might not be developed yet and the increase in blood pressure might affect the periventricular or intraventricular compartments —> heamorrages (capillaries are weak). The name is due to the place where it happens (germinative zone of the brain, where neurons are forming). This might give rise to neurological sequelae (cerebral palsy, mental retardation, seizure) CONGENITAL BRONCHOGENIC CYST It can happen that we have the formation of cysts over development —> abnormal budding of the respiratory bud (for example if a bronchus develops from the trachea). It usually happens in the anterior mediastinum, along the 0 trancheobronchial tree, in the lungs or in the pericardium. It might lead to infections or obstructions but in most cases patients are asymptomatic. The cyst usually has cartilage plates and submucosal glands in the wall (similar to normal microscopic anatomy of bronchi) CONGENITAL PULMONARY AIRWAYS MALFORMATION (CPAM) Multi cystic lung mass resulting from the proliferation of the terminal bronchioles structure with an associated suppression of alveolar growth. CPAM leads to abnormalities in bronchi branching, formation of fluid filled cysts and the establishment of a communication with the trachebronchial tree. If the mass grows too much it can lead to the displacement of other organs (Mediastinal shift, compression of the heart, compression of the venae cavae, compression of the oesophagus), lung hypoplasia, polyhydramnios and fetal hydrops. Symptoms: cough, shortness of breath, fever mktgLtypes mediastinalshift aka congenitallung overinflation CONGENITAL LOBAR EMPHYSEMA Overexpansion of one or more pulmonary lobes of the histologically normal lung without destruction of the alveolar walls —> air gets into the lungs but it struggles to be brought out. Certain areas of the lungs trap air inside and this causes a dilation. The word emphysema is not totally correct because this condition is due congenital reasons (there are just some areas that contain more air) and not due to the destruction of alveolar walls. It is usually idiopathic or due to a failure in cartilage development or due to an external or internal bronchial obstruction BRONCHIECTASIS Abnormal dilation of the walls of a bronchus. For example if a person is a heavy smoker the trachebronchial tree can be inflamed and the wall of the bronchi can be weakened. Where the wall is weak there might be dilation. There are some case in which this weakening is congenital (wall did not develop properly). It can be associated to Kartagener syndrome, cystic fibrosis or immunodeficiency disorders. This can cause cough, fever, foul smelling purulent mucus, dyspnea. It is a type of COPD (chronic obstructive pulmonary diseases) PULMONARY AGENESIS Failure of bronchial buds to develop —> lungs don’t develop —> no survival (the baby could survive only if this is unilateral) PULMONARY APLASIA Absence of lung tissue but presence of a rudimentary bronchus, again if unilateral the baby can survive PULMONARY HYPOPLASIA Poorly developed trachebronchial tree, usually on the right lung and associated with obstructive right-sided congenital heart defects. It is also found in association with congenital diaphragmatic hernia. It is more common on the left and posterolaterally (Bochdaleck hernias), but it can also be in other positions. (Morgagni hernias). It can also be caused by oligohydramnions due to renal agenesis (Potter syndrome)