Editing Lung (section)

== Development ==
{{Further|Sonic hedgehog#Lung development}}
The development of the human lungs arise from the [[laryngotracheal groove]] and develop to maturity over several weeks in the foetus and for several years following birth.<ref name="Sadler">{{cite book|last1=Sadler|first1=T.|title=Langman's medical embryology|url=https://archive.org/details/langmansmedicale00sadl_655|url-access=limited|date=2010|publisher=Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0-7817-9069-7|pages=[https://archive.org/details/langmansmedicale00sadl_655/page/n215 204]–207|edition=11th}}</ref>

The [[larynx]], [[trachea]], [[bronchus|bronchi]] and lungs that make up the respiratory tract, begin to form during the fourth week of [[human embryogenesis|embryogenesis]]<ref name=Moore_2002>{{cite book | author = Moore, K.L.|author2=Persaud, T.V.N. | title = The Developing Human: Clinically Oriented Embryology | edition = 7th| publisher = Saunders | year = 2002 | isbn = 978-0-7216-9412-2 }}</ref> from the [[lung bud]] which appears ventrally to the caudal portion of the [[foregut]].<ref>{{cite web|last1=Hill|first1=Mark|title=Respiratory System Development|url=https://embryology.med.unsw.edu.au/embryology/index.php/Respiratory_System_Development#cite_note-PMID20614584-22|website=UNSW Embryology|access-date=23 February 2016}}</ref>
[[File:Gray949.png|right|thumb|Lungs during development, showing the early branching of the primitive bronchial buds]]
The respiratory tract has a branching structure, and is also known as the respiratory tree.<ref name="Miura">{{Cite book|last1=Miura|first1=T|title=Multiscale Modeling of Developmental Systems|date=2008|volume=81|pages=291–310|doi=10.1016/S0070-2153(07)81010-6|pmid=18023732|series=Current Topics in Developmental Biology|isbn=9780123742537|chapter=Modeling Lung Branching Morphogenesis}}</ref> In the embryo this structure is developed in the process of [[Morphogenesis#Branching morphogenesis|branching morphogenesis]],<ref name="Ochoa-Espinosa">{{cite journal |last1=Ochoa-Espinosa |first1=A |last2=Affolter |first2=M |title=Branching morphogenesis: from cells to organs and back. |journal=Cold Spring Harbor Perspectives in Biology |date=1 October 2012 |volume=4 |issue=10 |pages=a008243 |doi=10.1101/cshperspect.a008243 |pmid=22798543|pmc=3475165 }}</ref> and is generated by the repeated splitting of the tip of the branch. In the development of the lungs (as in some other organs) the epithelium forms branching tubes. The lung has a left-right symmetry and each bud known as a [[lung bud|bronchial bud]] grows out as a tubular epithelium that becomes a bronchus. Each bronchus branches into bronchioles.<ref name="Wolpert">{{cite book|last1=Wolpert|first1=Lewis|title=Principles of development|date=2015|publisher=Oxford University Press|isbn=978-0-19-967814-3|pages=499–500|edition=5th}}</ref> The branching is a result of the tip of each tube bifurcating.<ref name="Miura"/> The branching process forms the bronchi, bronchioles, and ultimately the alveoli.<ref name="Miura"/> The four genes mostly associated with branching morphogenesis in the lung are the [[Hedgehog signaling pathway|intercellular signalling protein]] – [[sonic hedgehog]] (SHH), [[fibroblast growth factor]]s [[FGF10]] and FGFR2b, and [[bone morphogenetic protein]] [[bone morphogenetic protein 4|BMP4]]. FGF10 is seen to have the most prominent role. FGF10 is a [[paracrine signalling]] molecule needed for epithelial branching, and SHH inhibits FGF10.<ref name="Miura"/><ref name="Wolpert"/> The development of the alveoli is influenced by a different mechanism whereby continued bifurcation is stopped and the distal tips become dilated to form the alveoli.

At the end of the fourth week, the lung bud divides into two, the right and left [[lung bud|primary bronchial buds]] on each side of the trachea.<ref>{{cite book|last1=Sadler|first1=T.|title=Langman's medical embryology|url=https://archive.org/details/langmansmedicale00sadl_655|url-access=limited|date=2010|publisher=Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0-7817-9069-7|pages=[https://archive.org/details/langmansmedicale00sadl_655/page/n213 202]–204|edition=11th}}</ref><ref name="Larsen2001">{{cite book|last1=Larsen|first1=William J.|title=Human embryology|date=2001|publisher=Churchill Livingstone|location=Philadelphia|isbn=978-0-443-06583-5|page=144|edition=3.}}</ref> During the fifth week, the right bud branches into three secondary bronchial buds and the left branches into two secondary bronchial buds. These give rise to the lobes of the lungs, three on the right and two on the left. Over the following week, the secondary buds branch into tertiary buds, about ten on each side.<ref name=Larsen2001 /> From the sixth week to the sixteenth week, the major elements of the lungs appear except the [[Pulmonary alveolus|alveoli]].<ref name="isbn0-7817-5309-0">{{cite book |author=Kyung Won, Chung |title=Gross Anatomy (Board Review) |publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2005 |pages=156 |isbn=978-0-7817-5309-8 }}</ref> From week 16 to week 26, the bronchi enlarge and lung tissue becomes highly vascularised. Bronchioles and alveolar ducts also develop. By week 26, the terminal bronchioles have formed which branch into two respiratory bronchioles.<ref>{{cite book|last1=Larsen|first1=William J.|title=Human embryology|date=2001|publisher=Churchill Livingstone|location=Philadelphia|isbn=978-0-443-06583-5|page=134|edition=3.}}</ref> During the period covering the 26th week until birth the important [[blood–air barrier]] is established. Specialised [[alveolar cells|type I alveolar cells]] where [[gas exchange]] will take place, together with the [[alveolar cells|type II alveolar cells]] that secrete [[pulmonary surfactant]], appear. The surfactant reduces the [[surface tension]] at the air-alveolar surface which allows expansion of the alveolar sacs. The alveolar sacs contain the primitive alveoli that form at the end of the alveolar ducts,<ref>{{cite book|last1=Alberts|first1=Daniel|title=Dorland's illustrated medical dictionary|date=2012|publisher=Saunders/Elsevier|location=Philadelphia|isbn=978-1-4160-6257-8|page=56|edition=32nd}}</ref>
and their appearance around the seventh month marks the point at which limited respiration would be possible, and the premature baby could survive.<ref name=Sadler/>

=== Vitamin A deficiency ===
{{Main|Vitamin A deficiency}}
The developing lung is particularly vulnerable to changes in the levels of [[vitamin A]]. [[Vitamin A deficiency]] has been linked to changes in the epithelial lining of the lung and in the lung parenchyma. This can disrupt the normal physiology of the lung and predispose to respiratory diseases. Severe nutritional deficiency in vitamin A results in a reduction in the formation of the alveolar walls (septa) and to notable changes in the respiratory epithelium; alterations are noted in the extracellular matrix and in the protein content of the basement membrane. The extracellular matrix maintains lung elasticity; the basement membrane is associated with alveolar epithelium and is important in the blood-air barrier. The deficiency is associated with functional defects and disease states. Vitamin A is crucial in the development of the alveoli which continues for several years after birth.<ref name=Timoneda>{{cite journal |last1=Timoneda |first1=Joaquín |last2=Rodríguez-Fernández |first2=Lucía |last3=Zaragozá |first3=Rosa |last4=Marín |first4=M. |last5=Cabezuelo |first5=M. |last6=Torres |first6=Luis |last7=Viña |first7=Juan |last8=Barber |first8=Teresa |title=Vitamin A Deficiency and the Lung |journal=Nutrients |date=21 August 2018 |volume=10 |issue=9 |pages=1132 |doi=10.3390/nu10091132 |pmid=30134568 |pmc=6164133 |doi-access=free }}</ref>

=== After birth ===
At [[Childbirth|birth]], the baby's lungs are filled with fluid secreted by the lungs and are not inflated. [[Adaptation to extrauterine life#Breathing and circulation|After birth]] the infant's [[central nervous system]] reacts to the sudden change in temperature and environment. This triggers the first breath, within about ten seconds after delivery.<ref name="Medline2015">{{cite web |title=Changes in the newborn at birth |url=https://medlineplus.gov/ency/article/002395.htm |website=MedlinePlus Medical Encyclopedia }}</ref> Before birth, the lungs are filled with fetal lung fluid.<ref>{{cite journal|title=Fetal lung liquid secretion|journal=American Journal of Respiratory Cell and Molecular Biology|volume=25|issue=1|pages=8–10|doi=10.1165/ajrcmb.25.1.f211|pmid=11472968|year=2001|last1=O'Brodovich|first1=Hugh}}</ref>      After the first breath, the fluid is quickly absorbed into the body or exhaled. The [[vascular resistance|resistance]] in the lung's blood vessels decreases giving an increased surface area for gas exchange, and the lungs begin to breathe spontaneously. This accompanies [[Adaptation to extrauterine life|other changes]] which result in an increased amount of blood entering the lung tissues.<ref name= Medline2015 />

At birth, the lungs are very undeveloped with only around one sixth of the alveoli of the adult lung present.<ref name="Sadler"/> The alveoli continue to form into early adulthood, and their ability to form when necessary is seen in the regeneration of the lung.<ref name="Schittny">{{cite journal|last1=Schittny|first1=JC|last2=Mund|first2=SI|last3=Stampanoni|first3=M|title=Evidence and structural mechanism for late lung alveolarization|journal=American Journal of Physiology. Lung Cellular and Molecular Physiology|date=February 2008|volume=294|issue=2|pages=L246–254|doi=10.1152/ajplung.00296.2007|pmid=18032698|citeseerx=10.1.1.420.7315}}</ref><ref name="SchittnyJC">{{cite journal|last1=Schittny|first1=JC|title=Development of the lung|journal=Cell and Tissue Research|date=March 2017|volume=367|issue=3|pages=427–444|doi=10.1007/s00441-016-2545-0|pmid=28144783|pmc=5320013}}</ref> Alveolar septa have a double [[Capillary#Structure|capillary network]] instead of the single network of the developed lung. Only after the maturation of the capillary network can the lung enter a normal phase of growth. Following the early growth in numbers of alveoli there is another stage of the alveoli being enlarged.<ref>{{cite journal|last1=Burri|first1=PH|title=Fetal and postnatal development of the lung|journal=Annual Review of Physiology|date=1984|volume=46|pages=617–628|pmid=6370120|doi=10.1146/annurev.ph.46.030184.003153}}</ref>