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Lung Development and Cell Functions
Uğur Özçelik, MDHacettepe University Medical FacultyDepartment of Pediatric Pulmonology
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1. Morphogenesis
2. Adaptation to postnatal period
3. Growing and development
Development of respiratory system
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BEFORE BİRTH
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1. Embryonic stage (0-5,7 weeks post fertilization)
2. Pseudoglandular stage(7-16 weeks pf)
3. Canalicular stage(17-26 weeks pf)
4. Saccular (Alveolar) stage(27 weeks to term)
Morphogenesis
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Morphogenesis
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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
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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
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Carlson. Human embryology and developmental biology, 2009
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6 weeks5 weeks
Visceral pleura derived from splanchnic mesoderm;Parietal pleura derived from somatic mesoderm
Moore Respiratory System
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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
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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
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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.
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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
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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
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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
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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.
Newborn
Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35
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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
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Hislop AA,J Anat 2002;201:325
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8 weeks 16 weeks
18 weeks 24 weeks
Moore Respiratory System
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Morphogenesis
Hislop AA,J Anat 2002;201:325
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Hypoxia
Signaling molecules
Transcription factors
Extracellular matrix proteins and their receptors
NO
Fetal LungFetal breathing movements
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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
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Trancriptional mechanisms during pulmonary developmentFox 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
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Trancriptional mechanisms during pulmonary developmentTTF-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
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Trancriptional mechanisms during pulmonary development GATA-6
NF-1
Stat-3
Foxa1
NFATCosta 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
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Signaling molecules (secreted poypeptides) influencing lung morphogenesis and differentiation TGF-β BMP-4 FGF1,7,9,10 PLDGF EGF/TGF-α SHH VEGF-A HGF
IGF GM-CSF Wnt family
members
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
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Carlson. Human embryology and developmental biology, 2009
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Fetal breathing movementsMoore Respiratory System
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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
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Hypoxia Mother’s oxygen supply Uterine blood flow
Fetal breathing movementsPulmonary hypertensionAirway resistanceAlveolar numberAlveolar size
Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35
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AFTER BİRTH
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1. Morphogenesis
2. Adaptation to postnatal period
3. Growing and development
Development of respiratory system
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Adaptation to postnatal period
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
Hislop AA,J Anat 2002;201:325Haworth SG, Hislop AA. Semin in Neanatol 2003:8:1Hislop AA. Paediatr Resp Rew 2005;6:35
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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
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1. Morphogenesis
2. Adaptation to postnatal period
3. Growing and development
Development of respiratory system
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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
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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.
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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
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LUNG CELLS
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Lung cells Airway cells in bronchial and bronchiolar
epithelium and bronchial glandsBasalSecretoryClaraCiliatedNeuroendocrine cells
Proc Am Thorac Soc 2008;5:763 / 767
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Lung cells İnterstitial connective
tissue cellsSmooth muscleCartilageFibroblastsMyofibroblastsAdipose tissueNeural cells
Alveolar unit cellsType 1 cellsType 2 cellsFibroblasts in the interstitium
Proc Am Thorac Soc 2008;5:763 / 767
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Lung cells Pulmonary vascular
cellsEndothelial cells from different vascular structuresSmooth muscle cellsAdventitial fibroblasts
PleuraMesothelial cell layerPleuripotent submesothelial fibroblastsİntrapleural fatLymphatics
Hematopoeietic and lymphoid tissueLymphocytesPlasma cellsMegakaryocytesMacrophagesLangerhans cellsMast cellsEosinophilsNeutrophilsBasophils
Proc Am Thorac Soc 2008;5:763 / 767
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Lung cells Poorly defined cells
Stem cellsPerivascular epithelioid cellsPluripotent epithelial stem cellsMeningothelioid cellsEndothelial progenitor cells
Proc Am Thorac Soc 2008;5:763 / 767
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Function of lung cellsType I alveolar cells(pneumocytes)Across which gas exchangeoccurs after birth
Type II alveolar cells (secretory epithelial
cells)They form pulmonarysurfactant
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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.
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Function of lung cellsMucous 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
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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.
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Function of lung cellsClara cells: seen exclusively bronchial region of the lung. They have two roles;
1. They may recylcle surfactant
2. 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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Functions of lung cellsCells playing a role in lung defences Alveolar macrophages: Scavening particulates,
removing macromolecules, killing microorganisms, acting as a accessory and regulatory cells for a number of immune functions, recruiting and activating other inflammatory cells, repairing injured lung tissue, removing apaptotic cells and modulating normal lung physiology.
Mast cells: The major effector cells of allergic reactions
Dentritic cells: They are the primary resident antigen-presenting cell population in the lung and airway wall.
Neutrophils: Recognize, ingest and destroy pathogens.
Eosinophils: İmportant element in the pathogenesis of asthma and allergies
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