| Respiratory embryology |
| Alain C Borczuk, MD | |
| Dept of Pathology |
| Lung histology |
| Cast of Characters | |||
| Airways | |||
| Conducting | |||
| Respiratory | |||
| Vessels | |||
| Arteries, arterioles - pulmonary and bronchial | |||
| Capillaries | |||
| Veins/Venules and Lymphatics | |||
| Pleura- visceral and parietal | |||
| Slide 3 |
| Lung Histology: Conducting zone |
| Airways Conducting Zone | |||
| Trachea | |||
| Bronchi - ciliated and goblet cells, elastic tissue, smooth muscle, glands, cartilage | |||
| Bronchioles - (1 mm) - No cartilage or bronchial glands, ciliated lining,no goblet cells, smooth muscle | |||
| Cell types | |||
| CILIATED CELL - beating of cilia contribute to mucociliary elevator | |||
| GOBLET CELL - Mucus secretion | |||
| BASAL CELL - reserve cell | |||
| KULCHITSKY CELL - neuroendocrine cells. | |||
| Pulmonary Histology |
| Airways Respiratory Zone | ||||
| Terminal bronchiole to Respiratory bronchiole - lined by ciliated cells and CLARA CELLS; by transitional zone to RB, all Clara cells. | ||||
| Alveolar ducts/sacs | ||||
| Type I cells 90% of alveolar surface | ||||
| Type II cells | ||||
| Cell types | ||||
| CLARA CELLS - produce a component of surfactant and are the bronchiolar reserve cell | ||||
| TYPE I CELLS - Thin lining cell for gas exchange | ||||
| TYPE II CELLS - surfactant and alveolar reserve cell | ||||
| Slide 6 |
| Slide 7 |
| Laryngeal development |
| Week 4 | |||
| Respiratory primordium arises from distal/caudal pharynx | |||
| Laryngo-tracheal groove | |||
| Endodermal derivative of epithelium of larynx trachea and bronchi | |||
| Connective tissue, smooth muscle and cartilage from splanchnic mesenchyme surrounding the foregut | |||
| Laryngeal development |
| LT groove evaginates and forms LT diverticulum | |
| This becomes invested with splanchnic mesoderm to form lung bud | |
| This maintains a laryngeal inlet | |
| The septum that forms by folds and fusion keeps a septate inlet that becomes trachea and esophagus |
| Epithelium of the larynx |
| Endoderm of proximal/cranial end of LT tube and cartilage from neural crest origin | ||
| Formation of proximal larynx – cranial tube | ||
| Arytenoid swellings grow towards tongue | ||
| Airway gets closed off, eventually recanalizes | ||
| Laryngeal webs – Incomplete recanalization | ||
| Laryngeal atresia – ascites, hydrops and lungs do not properly form. | ||
| Trachea |
| Endoderm of distal LT tube | ||
| Epithelium of trachea and lung | ||
| Splanchnic mesenchyme | ||
| Connective tissue | ||
| 4th week | ||
| If esopahgeal separation from LT tube is incomplete, develops into TE fistula | ||
| Slide 12 |
| Slide 13 |
| Slide 14 |
| Bronchi/lungs |
| By 28 days – endodermal buds grow along with splanchnic mesenchyme | |
| By 35 days – Second degree bronchi, upper middle and lower on right, upper and lower on left | |
| By 42 days – Tertiary bronchopulmonary segments, 10 on the right and 8-9 on the left. | |
| Slide 16 |
| Slide 17 |
| Branching morphogenesis |
| By 24 weeks, 17 orders of bronchi and respiratory bronchioles (7 more after birth) | |
| Lungs grow to pleura – visceral pleura from splanchnic mesenchyme and parietal pleura from somatic mesoderm. | |
| Slide 19 |
| Slide 20 |
| Slide 21 |
| Lung Maturation |
| Pseudoglandular (5-17 weeks) | ||||
| No gas exchange zones | ||||
| Lung resembles an exocrine gland | ||||
| Canalicular (17-25 weeks) | ||||
| Terminal bronchioles enlarge and branch 2-3 respiratory bronchioles then 3-6 alveolar ducts. Terminal sacs begin to form | ||||
| VAscularized – caudal slower than cranial | ||||
| Terminal sac (25 weeks to 34 weeks) – blood flow and surfactant | ||||
| Epithelium thins to become type I like | ||||
| Capillaries grow in | ||||
| Blood air barrier forms | ||||
| Type I and type II cells | ||||
| Surfactant reduces surface tension allowing expansion. | ||||
| Alveolar period (late fetal to childhood) | ||||
| Surfactant | ||||
| Gas exchange | ||||
| Pulmonary vs systemic circulation | ||||
| Alveoli mature from age 3-8. Numbers increase from 50 million at birth and 300 million at age 8 (adult number) | ||||
| Early pseudoglandular 8 wk |
| Mid Pseudoglandular 13 wk |
| Late pseudoglandular-16 weeks |
| Mid-canalicular - 22 weeks |
| Slide 27 |
| Slide 28 |
| Slide 29 |
| Congenital malformations |
| Cystic adenomatoid malformations | ||
| Maturation arrest in lung segments | ||
| Azyous lobe | ||
| Superior apical bronchus grows medially instead of laterally; vein is at bottom of superior lobe fissure | ||
| Sequestration – | ||
| Accessory piece of lung that becomes disconnected from tracheobronchial tree and parasitizes systemic circulation from diaphragm. | ||
| Slide 31 |
| Breathing exercise |
| Begins pre-natally, allows branching to continue | ||
| Fluid is expelled from lungs at birth by vaginal pressure into capillaries and lymphatics | ||
| Fluid is needed for proper lung development | ||
| Insufficient fluid – decreased lung development | ||
| Insufficient breathing movements – decreased lung development (neurological) | ||
| Causes of Lung hypoplasia – diminished lung development |
| Oligohydramnios – insufficient amniotic fluid | ||
| Compression | ||
| Congenital diaphragmatic hernia – intestinal contents compress left hemithorax (usually) | ||
| Intrathoracic fluid or thoracic wall abnormality | ||
| Expansion of the lung activates a transcriptional program. |
| Stretching of myofibroblasts induces a transcriptional program that contributes to completion of distal proliferation and differentiation (TGF-B decrease) | |
| Lung expansion in utero by fluid is critical to proper lung development. |
| RDS-Respiratory distress syndrome |
| Low surfactant – Respiratory distress syndrome – usually due to pre-maturity, rarely due to surfactant protein deficiency (genetic cause) | ||||
| Surfactant is critical to reduce surface tension and allow lung expansion at the air fluid interface. | ||||
| Inadequate surfactant leads to alveolar collapse on expiration of air, and difficulty re-inflating | ||||
| Damage to the alveolus leads to cellular injury and exudation of proteins known as hyaline membranes (Hyaline membrane disease) | ||||
| Continued injury from ventilation of immature lungs can lead to chronic injury known as bronchopulmonary dysplasia. | ||||
| Steroids accelerate lung development and surfactant production | ||||
| Surfactant can also be administered | ||||
| Pulmonary vasculature |
| At birth, fetal lung circulation is a high pressure that must convert to a low pressure circulation. | ||
| As air enters the lung with the first breath, oxygen tension rises. | ||
| Increased nitric oxide production increases arterial vasodilation, reducing pulmonary arterial pressure. | ||
| Molecular determinants of branching morphogenesis |
| Much of this data is derived from transgenic animals. Knockout of genes and gain of function mutants | |
| Also experiments displacing mesenchyme and epithelium to new sites have been critical in understanding the crosstalk between epithelium and mesenchyma |
| Branching determinants |
| Removal of mesenchyme halts branching | |
| Non lung mesenchyme does not support branching | |
| Lung mesenchyme placed in trachea or salivary gland induces specific branching | |
| Proximal vs distal mesenchyme induces site appropriate epithelial cell development | |
| Mesenchymal factors are diffusable across membranes – No contact needed, but gradients are very local. | |
| Epithelial factors �crosstalk� to determine mesenchymal growth and differentiation. |
| FGF-fibroblast growth factor |
| Loss of epithelial FGF receptor leads to loss of branching | |
| FGF10 in mice from mesenchyme binds to FGFR2 on epithelial cells. | |
| Epithelial Shh (sonic hedgehog) shuts off FGF10 from mesenchyme, stopping growth. New buds form in Shh negative areas that have persistent FGF10 production | |
| Other FGF (e.g. FGF7) and other FGFR (e.g. FGFR3 and 4) may play a similar role in later stages of distal/alveolar lung development. |
| Factors in branching morphogenesis |
| Proliferation | ||
| Growth factors, factors that promote pluripotency | ||
| Differentiation | ||
| Transcription factors and downstream effectors leading to different cell types | ||
| Proximal and distal differences (e.g cartilage, type II cells) | ||
| Inhibition of proliferation | ||
| Growth eventually stops, also a key to branch points | ||
| Apoptosis | ||
| Structures must be remodeled in second wave of growth. | ||
| May deal with local proliferation excess. | ||
| Coordinated growth of different cell populations – �crosstalk� | ||
| Elements may be intracellular pathways, cellular receptor specificity, as well as diffusable factors with very local gradients | ||
| Differential adhesion. | ||
| Cell to cell, cell to matrix. | ||
| Adhesion molecules may be expressed reducing cellular fluidity, fostering attachment of epithelium to mesenchyme via common extracellular matrix proteins | ||
| Branching parameters |
| BMP4 may prevent proximal type differentiation, allowing cells to accept signals for distal development. | ||
| TTF1 and HNF3B may promote differentiation towards surfactant producing cells. | ||
| Shh may induce proliferation and differentiation in mesenchyme and inhibit epithelial proliferation signals (FGF10). | ||
| TGF-B may induce extracellular matrix production, which in turn may further anchor and stabilize epithelial cells. | ||
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| Slide 45 |