Lung Development and Cell Functions

Uğur Özçelik, MDHacettepe University Medical FacultyDepartment of Pediatric Pulmonology

1. Morphogenesis

2. Adaptation to postnatal period

3. Growing and development

Development of respiratory system

BEFORE BİRTH

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

Morphogenesis

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

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

Carlson. Human embryology and developmental biology, 2009

6 weeks5 weeks

Visceral pleura derived from splanchnic mesoderm;Parietal pleura derived from somatic mesoderm

Moore Respiratory System

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

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

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.

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

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

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

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

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

Hislop AA,J Anat 2002;201:325

8 weeks 16 weeks

18 weeks 24 weeks

Moore Respiratory System

Morphogenesis

Hislop AA,J Anat 2002;201:325

Hypoxia

Signaling molecules

Transcription factors

Extracellular matrix proteins and their receptors

NO

Fetal LungFetal breathing movements

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

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

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

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

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

Carlson. Human embryology and developmental biology, 2009

Fetal breathing movementsMoore Respiratory System

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

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

AFTER BİRTH

1. Morphogenesis

2. Adaptation to postnatal period

3. Growing and development

Development of respiratory system

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

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

1. Morphogenesis

2. Adaptation to postnatal period

3. Growing and development

Development of respiratory system

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

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.

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

LUNG CELLS

Lung cells Airway cells in bronchial and bronchiolar

epithelium and bronchial glandsBasalSecretoryClaraCiliatedNeuroendocrine cells

Proc Am Thorac Soc 2008;5:763 / 767

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

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

Lung cells Poorly defined cells

Stem cellsPerivascular epithelioid cellsPluripotent epithelial stem cellsMeningothelioid cellsEndothelial progenitor cells

Proc Am Thorac Soc 2008;5:763 / 767

Function of lung cellsType I alveolar cells(pneumocytes)Across which gas exchangeoccurs after birth

Type II alveolar cells (secretory epithelial

cells)They form pulmonarysurfactant

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.

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

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.

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.

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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