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Lung Development and Cell Functions

Lung Development and Cell Functions. Uğur Özçelik, MD Hacettepe University Medical Faculty Department of Pediatric Pulmonology. Development of respiratory system. Morphogenesis Adaptation to postnatal period Growing and development. BEFORE BİRTH. Morphogenesis.

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Lung Development and Cell Functions

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  1. Lung Development and Cell Functions Uğur Özçelik, MD Hacettepe University Medical Faculty Department of Pediatric Pulmonology

  2. Development of respiratory system • Morphogenesis • Adaptation to postnatal period • Growing and development

  3. BEFORE BİRTH

  4. Morphogenesis • Embryonic stage (0-5,7 weeks post fertilization) • Pseudoglandular stage(7-16 weeks pf) • Canalicular stage(17-26 weeks pf) • Saccular (Alveolar) stage(27 weeks to term)

  5. Morphogenesis

  6. Embryonic stage(up to 7 weeks of gestation) • The lung bud appears as a ventral diverticulum of foregut during the 4.weeks of the gestation. • By 6 weeks, the two lungs can be distinguished as separate organs in thorax. Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  7. Embryonic stage(up to 7 weeks of gestation) • Lobar airways lined with endoderm are established within the surrounding mesenchyme. • Endoderm give rise to specialized epithelial cells of the lung. • All other elements of the airway wall orginate from the mesenchyme Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  8. Carlson. Human embryology and developmental biology, 2009

  9. 5 weeks 6 weeks Visceral pleura derived from splanchnic mesoderm; Parietal pleura derived from somatic mesoderm Moore Respiratory System

  10. Pulmonary circulation • As early as 34 days of gestation, each lung bud is supplied by a pulmonary artery extending from the outflow tract of the heart. • On the ventral side of the each lung bud, a pulmonary vein connects to the prospective left atrium. • Between these arteries and veins lies mesenchymal capillary plexus. Hislop AA,J Anat 2002;201:325

  11. Pseudoglandular stage(7-17 weeks of gestation) • Smooth muscle cells are present in human trachea and lobar bronchi by 8-10 weeks of gestation and are innervated from as early as 8 weeks of gestation. • Smooth muscle, closely followed by cartilage, submucosal glands and connective tissue, develops in the newly formed airway wall, and the epithelium begins to differentiate. • From 11 weeks of gestation, the epithelium differentiates into ciliated, goblet and basal cells, Clara cells. Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  12. Pseudoglandular stage(7-17 weeks of gestation) • As each new bud forms, a halo of endothelial tubules surrounds them to form pulmonary arteries and veins. • Preacinar branching of both arteries and veins complete by 17 weeks of gestation. • The first layer of smooth musce cells found around the newlly formed arteries. • The bronchial arteries appear from the descending aorta from 8 weeks of gestation.

  13. Canalicular stage(17-27 weeks of gestation) • The preacinar airways increase in size • Peripheral airways continue to divide to form the prospective respiratory bronchioli. • Further centrifugal division of the airway buds into the mesenchyme results in all preacinar airways to the level of the terminal bronchioli being present by 17th week of gestation. Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  14. Canalicular stage(17-27 weeks of gestation) • By 20-22 weeks of gestation, flat, elongated type I and cuboidal type II alveolar epithelial cells can be identified lining all saccular air spaces. • Type II cells develop lameller bodies around 24 weeks of gestation. • The arteries and veins continue to develop alongside to airways. Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  15. Canalicular stage(17-27 weeks of gestation) • During this stage, thinning of the epithelium at the lung periphery by underlying capillaries leads to the formation of blood-gas barrier as thin as that of the adult. • By the 24 weeks of gestation the airways have the same wall structure as they have in the adult. Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  16. Newborn Saccular (Alveolar) stage(27 weeks to term) • The edges of the saccules contain discrete bundles of elastin and muscle, which form small crests subdividing the walls. • Between 28-32 weeks of gestation, these crests alongate to produce alveoli. Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  17. Saccular (Alveolar) stage(27 weeks to term) • The number of the alveoli increases with gestational age, and by term approximately 150 million alveoli have formed, between one-third and one-half of the adult number. • Alveolar surface area increases a linear relationship to age and bodyweight. Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  18. Hislop AA,J Anat 2002;201:325

  19. 8 weeks 16 weeks 18 weeks 24 weeks Moore Respiratory System

  20. Morphogenesis Hislop AA,J Anat 2002;201:325

  21. Transcription factors Hypoxia Fetal Lung Signaling molecules Fetal breathing movements Extracellular matrix proteins and their receptors NO

  22. Transcription factors(TF) • “sequence spesific DNA binding factor” • TF is a protein that binds to spesific DNA sequences and thereby controls the transfer (or transcription) of genetic information from DNA to RNA. • blocking RNA polymerase promoting

  23. Trancriptional mechanisms during pulmonary development Fox a2 formation of foregut endoderm (Hnf3-β) influences of expression of spesific genes in the respiratory epithelium regulating surfactant protein and phospholipit production Costa TH. Am J Physiol Lung Cell Mol Physiol 2001;280: L823Kumar VH. Adv Clin Chem 2005:40:261Varanou A.Br J Pharma 2008:155:316

  24. Trancriptional mechanisms during pulmonary development TTF-1 regulates number of genes for lung (Nkx2.1) development and function (surfactan proteins, fluid and electrolyte transport, host defence, vasculogenesis) Costa TH. Am J Physiol Lung Cell Mol Physiol 2001;280: L823Kumar VH. Adv Clin Chem 2005:40:261Varanou A.Br J Pharma 2008:155:316

  25. Trancriptional mechanisms during pulmonary development • GATA-6 • NF-1 • Stat-3 • Foxa1 • NFAT Costa TH. Am J Physiol Lung Cell Mol Physiol 2001;280: L823Kumar VH. Adv Clin Chem 2005:40:261Varanou A.Br J Pharma 2008:155:316

  26. TGF-β BMP-4 FGF1,7,9,10 PLDGF EGF/TGF-α SHH VEGF-A HGF IGF GM-CSF Wnt family members Signaling molecules (secreted poypeptides) influencing lung morphogenesis and differentiation Costa TH. Am J Physiol Lung Cell Mol Physiol 2001;280: L823Kumar VH. Adv Clin Chem 2005:40:261Varanou A.Br J Pharma 2008:155:316

  27. Carlson. Human embryology and developmental biology, 2009

  28. Fetal breathing movements Moore Respiratory System

  29. Hypoxia • Oxygen requirments are lower in fetal life than they are postnatally. • The shift in the fetal hemoglobin equilibration curve increases oxygen accessibility. Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1

  30. Hypoxia Mother’s oxygen supply Uterine blood flow Fetal breathing movements Pulmonary hypertension Airway resistance Alveolar number Alveolar size Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  31. AFTER BİRTH

  32. Development of respiratory system • Morphogenesis • Adaptation to postnatal period • Growing and development

  33. Pulmonary vascular resistance falls and blood flow increases immediately after birth. Nitric oxide helps to modulate pulmonary vascular resistance in utero and contributes to the postnatal fall in resistance Bidirectional shunting can occur as long as the ductus arteriosus remains open. The pulmonary arterial wall thickness decreases and lumen diameter increases %80 O2 placenta %58 O2 Adaptation to postnatal period Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  34. Adaptation to postnatal period • Endothelial and smooth muscle cells become thinner. • At the first 1-2 weeks of life the number of the contractile myofilaments reduce. Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  35. Development of respiratory system • Morphogenesis • Adaptation to postnatal period • Growing and development

  36. Postnatal development • The proliferation of alveoli, with their accompanying vessels, continous after birth until the adult number of alveoli is reached by 2-3 years of age. • Stabilization of the morphological pattern of the lungs does not occur until about 8 years of age. • Alveolar size and surface area continue to increase beyond adolescence. Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  37. Postnatal development • Airway calibre is large relative to lung volume at birth. • The airways initially increase in size in linear-fashion in line with antenatal growth, then slowing after the first year. • Calibre increases approximately 2 fold between 22 wks.gestation to 8 months of postnatal age, and 2-3 fold between birth and adulthood.

  38. Postnatal development • The submucosal glands mass being greater in children than in adults. • Boys have more alveoli than girls for a given height at all ages. • Girls have wider and/or shorter airways than boys during early childhood. • In adulthood males have relatively large airways. Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35

  39. LUNG CELLS

  40. Lung cells • Airway cells in bronchial and bronchiolar epithelium and bronchial glandsBasalSecretoryClaraCiliatedNeuroendocrine cells Proc Am Thorac Soc 2008;5:763 / 767

  41. İnterstitial connective tissue cellsSmooth muscleCartilageFibroblastsMyofibroblastsAdipose tissueNeural cells Alveolar unit cellsType 1 cellsType 2 cellsFibroblasts in the interstitium Lung cells Proc Am Thorac Soc 2008;5:763 / 767

  42. Pulmonary vascular cellsEndothelial cells from different vascular structuresSmooth muscle cellsAdventitial fibroblasts PleuraMesothelial cell layerPleuripotent submesothelial fibroblastsİntrapleural fatLymphatics Hematopoeietic and lymphoid tissueLymphocytesPlasma cellsMegakaryocytesMacrophagesLangerhans cellsMast cellsEosinophilsNeutrophilsBasophils Lung cells Proc Am Thorac Soc 2008;5:763 / 767

  43. Lung cells • Poorly defined cellsStem cellsPerivascular epithelioid cellsPluripotent epithelial stem cellsMeningothelioid cellsEndothelial progenitor cells Proc Am Thorac Soc 2008;5:763 / 767

  44. Type I alveolar cells (pneumocytes) Across which gas exchange occurs after birth Type II alveolar cells (secretory epithelial cells) They form pulmonary surfactant Functionof lung cells

  45. Function of lung cells Ciliated cells • Responsible for propelling mucus from the peripheral airways to pharynx • Mucociliary transport is an important defence mechanism of the lungs.

  46. Function of lung cells Mucous glands • Present in large and small bronchi • The chief source of airway secretion • Contain both serous and mucous mucus-producing cells • Mucous glands, goblet cells

  47. Function of lung cells • Basis cells: commonly seen in within pseudostratified columnar epithelium, is undifferentiated and may be precursor of ciliated or secretory cells. • Brush cells: has a dense tuft of broad, short microvilli and is only rarely seen within the conducting airways and alveolar space. • Neuroendocrin cells: Feyrter or Kulchitsky cells: Belongs to APUD cells. They contain a variety of vasoactive peptides, including serotonin and kinins.

  48. Function of lung cells Clara cells: seen exclusively bronchial region of the lung. They have two roles; • They may recylcle surfactant • They are capable of actively transporting sodium from their apical to their basal side and thus may be involved in the reabsorption of fluid from the distal lung unit.

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