Лекция 08

1. Лекция 08 Формирование лёгких

2. Производные переднего отдела энтодермы • Носовая полость. Contains hairs to filter out particulate matter, and olfactory mucosa to provide a sense of smell. • Глотка. Acts as a resonant cavity for speech also serves as part of the alimentary tract. • Гортань. Contains vocal folds which generate the voice. The larynx and all structures beyond can be isolated from the pharynx during swallowing. • Трахея. Provides a flexible connection between the lungs and the more rigid structures of the upper respiratory tract. • Бронхи. The trachea divides into 2 primary bronchi which lead into the left and right lungs. Secondary (etc) bronchii then ramify throughout the lungs. • Бронхиолы. The final conducting portions of the lungs, less than 1mm in diameter and devoid of cartilage, which undergo more branching divisions The final segments are called terminal bronchioles, which occur at about the 16th level of branching and lead into the respiratory portion of the lung.

3. Ларинготрахейный желоб –производное кишечной трубки (дно кишечной трубки между четвёртой пары глоточных карманов), роль Tbx4, трахейно-пищевая фистула(по Gilbert, 2003).

4. S. Mund

5. Формирование производных из верхней части энтодермы - из глоточных карманов (6 пар карманов) (по Gilbert, 2003)

6. Сурфактант • Клетки формирующихся альвеол, секретируют жидкость, омывающую легкие – сурфактант. Сурфактант (С) придаёт клеткам альвеол способность не слипаться при соприкосновении. • С - состоит из фосфолипидов (сфингомиелин и лецитин). • У человека С достигает физиологического уровня на 34 неделе беременности, поэтому недоношенных младенцев помещают до созревания С на респираторы.

7. Стадии развития лёгких (человек) • Эмбриональная стадия (3-7 weeks) Initial budding and branching of the lung buds from the primitive foregut. Ends with the development of the presumptive broncho-pulmonary segements. • Псевдогландулярная стадия (7-16) weeks Further branching of the duct system (up to 21 further orders) generates the presumptive conducting portion of the respiratory system up to the level of the terminal bronchioles. At this time the future airways are narrow with little lumens and a pseudostratified squamous epithelium. They are embedded within a rapidly proliferating mesenchyme. The structure has a glandular appearance. • Каналикулярная стадия (16-24) weeks The onset of this phase is marked by extensive angiogenisis within the mesenchyme that surrounds the more distal reaches of the embryonic respiratory system to form a dense capillary network. The diameter of the airways increases with a consequent decrease in epithelial thickness to a more cuboidal structure. The terminal bronchioles branch to form several orders of respiratory bronchioles. Differentiation of the mesenchyme progresses down the developing respiratory tree, giving rise to chondrocytes, fibroblasts and myoblasts.

8. Стадии развития лёгких (человек) • Стадия терминальных мешочков (24-36) weeks Branching and growth of the terminal sacs or primitive alveolar ducts. Continued thinning of the stroma brings the capillaries into apposition with the prospective alveoli. Functional type-II pneumonocytes differentiate via several intermediate stages from pluripotent epithelial cells in the prospective alveoli. Type I pneumonocytes differentiate from cells with a type-II like phenotype. These cells then flatten, increasing the epithelial surface area by dilation of the saccules, giving rise to immature alveoli. By 26 weeks, a rudimentary though functional blood/gas barrier has formed. Maturation of the alveoli continues by further enlargement of the terminal sacs, deposition of elastin foci and development of vascularised septae around these foci. The stroma continues to thin until the capillaries protrude into the alveolar spaces. • Альвеолярная стадия (36 weeks - term/adult) Maturation of the lung indicated by the appearance of fully mature alveoli begins at 36 weeks, though new alveoli will continue to form for approximately three years. A decrease in the relative proportion of parenchyma to total lung volume still contributes significantly to growth for 1 to 2 years after birth, thereafter all components grow proportionately until adulthood.

9. Дыхательная трубка • The conducting portion of the respiratory tract is lined with a pseudostratified columnar epithelium. The upper reaches, from the trachea to the mid-sized bronchioles, consist of three main cell types; • Ciliated cells. Possess motile cillia which extent into the lumen of the airway and sweep upwards in coordinated waves. Their action moves the mucous coat upwards along with trapped particles to be expelled. • Goblet cells. Produce and secrete the mucous covering of the airways. This humidifies inhaled air and traps foreign particles, protecting the deeper portions of the lung. • Basal cells. Do not extend into the lumen and are the stem cells for other cell types. • In addition there are sensory brush cells and endocrine granule cells (more common in the foetal lung). The submucosa of the trachea and bronchi contain many mixed seromucous glands (though predominantly mucous) which add their secretions to those of the goblet cells. Clara cells secrete a form of surfactant. They predominate in the terminal bronchioles, though they are not restricted to this location.

10. Респираторный отдел лёгких • This consists of respiratory bronchioles, which lead to the alveolar components. Respiratory bronchioles are similar in construction to terminal bronchioles, except that the walls are periodically interrupted by alveoli which are capable of gas exchange. When the proportion of interspersed alveoli increases to the degree where they occupy the majority of the surface of the airway, the passages are termed alveolar ducts. Alveolar ducts end in clusters of alveoli termed alveolar sacs. The alveolus can be considered is the unit of gas exchange. It's walls are composed of two epithelial cell types; • Type-I pneumonocytes are squamous pulmonary epithelial cells that form about 95% of the alveolar surface. They is an extremely thin and form part of the blood/air interface, the gasses diffusing through the cell. • Type-II pneumocytes are cuboidal and generally located at the junctions between alveoli. They secrete phospholipid-rich pulmonary surfactant. • Small numbers of sensory brush cells are also present, as are fibroblasts and macrophages in the interstitial spaces. Alveoli are in intimate contact with capiliaries of the pulmonary vasculature. The blood/air barrier is therefore composed of pulmonary surfactant, type-I cells, basement membrane, and capillary endothelium (blood blasma and RBC membrane).

11. Региональная специфичность мезодермы дыхательного отдела • Региональная специфичность морфогенеза путём ветвления, достигается региональной специфичностью мезодермы, взаимодействующей с энтодермальными зачатками легких.

12. Развитие лёгкого у млекопитающего путём ветвления (Gilbert, 2003)

13. Индуцирующее влияние специфичной для данного раздела мезодермы на энтодермальный зачаток легкого (по Gilbert, 2003)

14. Эпителий и мезенхима индуцируют ветвление энтодермы

15. Роль морфогена BMP4 в морфогенезе легких

17. Контроль образования зачатков легких в ходе морфогенеза путём ветвленияDiagram incorporates models proposed by Bellusci and coworkers (1997) and Lebeche and coworkers (1999). (A) Local expression of FGF-10 in the mesenchyme induces chemo-attraction and epithelial growth. (B) As the bud is induced, FGF-10 is inhibited by Shh expressed at the tips and by TGFβ-1 expressed throughout the subepithelial region. Concomitantly, proliferation is inhibited at the tips by FGF-10-mediated up-regulation of BMP-4. (C) These mechanisms limit bud outgrowth and expansion, resulting in cleft formation. FGF-10-expressing cells appear at other sites to induce a new generation of buds. At the cleft, low levels of FGF-10 are maintained by subepithelial TGFβ-1, which also induces synthesis of extracellular matrix components deposited in the epithelial-mesenchymal interface and prevents local budding.

18. Regulation of RA signaling at the onset of lung development (left) and during branching morphogenesis (right) based on data from Malpel and coworkers (2000). At an initial stage, mesothelial cells expressing RALDH-2 synthesize RA, which diffuses and activates RA signaling ubiquitously (RAR/RXR in gray boxes represents activated RA signaling; RAR/RXR encircled in white boxes represents suppressed RA signaling). During branching, RA signaling is suppressed in the epithelium by P450RAI-mediated RA metabolism and by COUP-TFII inhibition of RAR/RXR activation of target genes.

19. Стадии развития лёгких (человек)S. Mund

20. Стадии развития лёгких (человек)(Rothstein)

21. In the architecturally complex lung, cells of multiple germinal lineages interact both during morphogenesis and to maintain adult lung structure. Even within derivatives of a single germ layer, cells become subdivided into separate cell lineage "zones". For example, the endoderm generates least four distinct epithelial regions, each with a different cellular composition (see Figure above). • Additional cell types, including airway smooth muscle, fibroblasts, and the vasculature, are derived from mesoderm. • Airway and alveolar architecture, and in turn, function, result from interaction among epithelium, smooth muscle, fibroblasts, and vascular cells, all within an elaborate structural matrix of connective tissue. • The complexity of even this oversimplified view, which omits pulmonary neuroepithelial cells and bodies, innervation, and classical hematopoietically-derived cells such as dendritic cells, mast cells, and macrophages, has hindered identification of lung stem cells and patterns of cell migration during tissue renewal. • Nevertheless, the prevailing view is that airway basal and Clara cells and alveolar type II cells serve as epithelial progenitors. • Cell lineages in the mesodermal compartments remain less well understood.

22. Можно ли восстанавливать утраченные части лёгкого? (S. Mund)

23. The origins of the pulmonary vasculature remain obscure. Recent work, however, has shown that the paired-related homeobox gene, Prx1, is required for lung vascularization. Initial studies using fetal mouse lung tissue revealed that Prx1 localizes to differentiating endothelial cells (ECs) within the distal fetal lung mesenchyme, as well as within ECs forming vascular networks later in development. To begin to determine whether Prx1 promotes EC differentiation, rat and mouse fetal lung mesodermal cells were stably transfected with full-length Prx1 cDNA, resulting in their morphological transformation to an EC-like phenotype. In addition, Prx1-transformed cells acquired the ability to form vascular networks on Matrigel. Thus, Prx1 might function by promoting both pulmonary EC differentiation within the fetal lung mesoderm (i.e. vasculogenesis), as well as their subsequent incorporation into vascular networks (i.e. angiogenesis). To understand how Prx1 participates in this latter process, we focused on tenascin-C (TN-C), an extracellular matrix (ECM) protein induced by Prx1. Importantly, a TN-C-rich ECM surrounds Prx1-positive pulmonary vascular networks both in vivo and in tissue culture. Furthermore, we showed that TN-C is required for Prx1-dependent vascular network formation on Matrigel. Finally, to determine whether these results were relevant in vivo, we examined newborn Prx1-wild type (+/+) and -null (-/-) mice, and showed that Prx1 is critical for expression of TN-C expression and lung vascularization in vivo. Collectively, these studies provide a molecular framework for current work aimed at understanding how Prx1 controls vasculogenesis and angiogenesis in the developing lung.

24. Можно ли восстанавливать утраченные части лёгкого? (S. Mund)

25. Можно ли восстанавливать утраченные части лёгкого? (S. Mund)

26. Можно ли восстанавливать утраченные части лёгкого? (S. Mund)

27. Можно ли восстанавливать утраченные части лёгкого? (S. Mund).