View source for Pulmonary surfactant

{{Short description|Complex of phospholipids and proteins}}
{{cs1 config|name-list-style=vanc}}
[[File:An alveolus, is an anatomical structure that has the form of a hollow cavity. Mainly found in the lung, the pulmonary alveoli are spherical outcroppings of the respiratory bronchioles and are the.png|thumb|300px|[[Pulmonary alveolus|Alveoli]] are the spherical outcroppings of the [[respiratory bronchioles]].]]
'''Pulmonary surfactant''' is a surface-active complex of [[phospholipid]]s and [[protein]]s formed by [[Type II cells|type II alveolar cells]].<ref name="Bernhard">{{cite journal |last1=Bernhard |first1=W |title=Lung surfactant: Function and composition in the context of development and respiratory physiology. |journal= Annals of Anatomy |date=November 2016 |volume=208 |pages=146–150 |doi=10.1016/j.aanat.2016.08.003 |pmid=27693601}}</ref> The proteins and lipids that make up the [[surfactant]] have both [[hydrophilic]] and [[hydrophobic]] regions. By [[adsorption|adsorbing]] to the air-water [[Interface (chemistry)|interface]] of [[pulmonary alveolus|alveoli]], with hydrophilic head groups in the water and the hydrophobic tails facing towards the air, the main lipid component of the surfactant, [[dipalmitoylphosphatidylcholine]] (DPPC), reduces [[surface tension]].

<!-- History, society and culture -->
As a medication, [[Pulmonary surfactant (medication)|pulmonary surfactant]] is on the [[WHO Model List of Essential Medicines]], the most important medications needed in a basic [[health system]].<ref name=WHO2015E>{{cite web |url=https://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf |title=19th WHO Model List of Essential Medicines (April 2015) |date=April 2015 |access-date=May 10, 2015 |publisher=WHO }}</ref>

==Function==

* To increase [[pulmonary compliance]].
* To prevent [[atelectasis]] (collapse of the alveoli or atriums) at the end of expiration.
* To facilitate recruitment of collapsed airways.

Alveoli can be compared to gas in water, as the alveoli are wet and surround a central air space.  The [[surface tension]] acts at the air-water interface and tends to make the bubble smaller (by decreasing the surface area of the interface). The gas pressure (''P'') needed to keep an equilibrium between the collapsing force of [[surface tension]] (''γ'') and the expanding force of gas in an alveolus of radius ''r'' is expressed by the [[Young–Laplace equation]]:

:<math> P = \frac{2\gamma}{r} </math>

===Compliance===
[[Compliance (physiology)|Compliance]] is the ability of [[lung]]s and [[thorax]] to expand. 
Lung compliance is defined as the volume change per unit of pressure change across the lung. Measurements of lung volume obtained during the controlled inflation/deflation of a normal lung show that the volumes obtained during deflation exceed those during inflation, at a given pressure. This difference in inflation and deflation volumes at a given pressure is called [[hysteresis#Respiratory physiology|hysteresis]] and is due to the air-water surface tension that occurs at the beginning of inflation. However, surfactant decreases the alveolar [[surface tension]], as seen in cases of premature infants with [[infant respiratory distress syndrome]].  The normal surface tension for water is 70 dyn/cm (70&nbsp;mN/m) and in the lungs, it is 25 dyn/cm (25&nbsp;mN/m); however, at the end of the expiration, compressed surfactant phospholipid molecules decrease the surface tension to very low, near-zero levels. Pulmonary surfactant thus greatly reduces [[surface tension]], increasing compliance allowing the lung to inflate much more easily, thereby reducing the work of breathing.  It reduces the pressure difference needed to allow the lung to inflate. The lung's compliance, and ventilation decrease when [[Lung parenchyma|lung tissue]] becomes diseased and [[Fibrosis|fibrotic]].<ref>{{cite web|title=Alveoli and the Breathing Process|url=http://www.medicalassistantonlineprograms.org/alveoli/|access-date=2013-10-30|archive-date=2015-05-18|archive-url=https://web.archive.org/web/20150518094937/http://www.medicalassistantonlineprograms.org/alveoli/|url-status=dead}}{{MEDRS|date=May 2015}}</ref>

===Alveolar size regulation===

As the alveoli increase in size, the surfactant becomes more spread out over the surface of the liquid.  This increases surface tension effectively slowing the rate of expansion of the alveoli.  This also helps all alveoli in the lungs expand at the same rate, as one that expands more quickly will experience a large rise in surface tension slowing its rate of expansion.  It also means the rate of shrinking is more regular as if one reduces in size more quickly the surface tension will reduce more, so other alveoli can contract more easily than it can. Surfactant reduces surface tension more readily when the alveoli are smaller because the surfactant is more concentrated.

===Prevention of fluid accumulation and maintenance of dryness of airways===
Surface tension draws fluid from capillaries to the alveolar spaces. Surfactant reduces fluid accumulation and keeps the airways dry by reducing surface tension.<ref>{{cite book 
|author=West, John B. 
|title=Respiratory physiology-- the essentials 
|publisher=Williams & Wilkins 
|location=Baltimore 
|year=1994 
|isbn=0-683-08937-4 
|url-access=registration 
|url=https://archive.org/details/respiratoryphysi00west 
}}{{page needed|date=May 2015}}</ref>

===Innate immunity===
Surfactant immune function is primarily attributed to two proteins: [[Surfactant protein A|SP-A]] and [[Surfactant protein D|SP-D]]. These proteins can bind to sugars on the surface of pathogens and thereby [[opsonize]] them for uptake by phagocytes. It also regulates inflammatory responses and interacts with the adaptive immune response. Surfactant degradation or inactivation may contribute to enhanced susceptibility to lung inflammation and infection.<ref>{{cite journal |doi=10.1159/000078172 |pmid=15211087 |title=Host Defense Functions of Pulmonary Surfactant |journal=Biology of the Neonate |volume=85 |issue=4 |pages=326–32 |year=2004 |last1=Wright |first1=Jo Rae |s2cid=25469141 }}</ref>

==Composition==
* ~40% [[dipalmitoylphosphatidylcholine]] (DPPC);<ref name="NkadiMerritt2009">{{cite journal|last1=Nkadi|first1=Paul O.|last2=Merritt|first2=T. Allen|last3=Pillers|first3=De-Ann M.|title=An overview of pulmonary surfactant in the neonate: Genetics, metabolism, and the role of surfactant in health and disease|journal=Molecular Genetics and Metabolism|volume=97|issue=2|year=2009|pages=95–101|issn=1096-7192|doi=10.1016/j.ymgme.2009.01.015|pmc=2880575|pmid=19299177}}</ref>
* ~40% other [[phospholipid]]s (PC);<ref name="NkadiMerritt2009" />
* ~10% surfactant [[proteins]] ([[Surfactant protein A|SP-A]], [[Pulmonary surfactant-associated protein B|SP-B]], [[Surfactant protein C|SP-C]] and [[Surfactant protein D|SP-D]]);<ref name="NkadiMerritt2009" />
* ~10% neutral [[lipids]] ([[Cholesterol]]);<ref name="NkadiMerritt2009" />
* Traces of other [[Chemical substance|substances]].

===Lipids===

====DPPC====
[[Dipalmitoylphosphatidylcholine]] (DPPC) is a [[phospholipid]] with two 16-carbon saturated chains and a [[phosphate]] group with quaternary amine group attached. The DPPC is the strongest surfactant molecule in the pulmonary surfactant mixture. It also has a higher compaction capacity than the other phospholipids, because the apolar tail is less bent. Nevertheless, without the other substances of the pulmonary surfactant mixture, the DPPC's [[adsorption]] kinetics is very slow. This happens primarily because the phase [[transition temperature]] between [[gel]] to [[liquid crystal]] of pure DPPC is  41.5&nbsp;°C, which is higher than the [[Human body temperature|human body's temperature]] of 37&nbsp;°C.<ref>{{cite journal |pmid=276866 |title=Nature of the gel to liquid crystal transition of synthetic phosphatidylcholines |journal=Proceedings of the National Academy of Sciences of the United States of America  |volume=75 |issue=5 |pages=2258–2260 |year=1978 |last1=Albon |first1=Norman |doi=10.1073/pnas.75.5.2258 |pmc=392531|bibcode=1978PNAS...75.2258A |doi-access=free }}</ref>

====Other phospholipids====
Phosphatidylcholine molecules form ~85% of the lipid in surfactant and have saturated acyl chains. Phosphatidylglycerol (PG) forms about 11% of the lipids in the surfactant, it has unsaturated fatty acid chains that fluidize the lipid monolayer at the interface. Neutral lipids and cholesterol are also present. The components for these lipids diffuse from the blood into type II alveolar cells where they are assembled and packaged for secretion into secretory organelles called [[lamellar bodies]].{{citation needed|date=May 2015}}

===Proteins===

[[Proteins]] make up the remaining 10% of the surfactant.  Half of this 10% is [[plasma proteins]] but the rest is formed by the [[apolipoprotein]]s, surfactant proteins SP-A, SP-B, SP-C, and SP-D. The apolipoproteins are produced by the secretory pathway in type II cells. They undergo much post-translational modification, ending up in the lamellar bodies. These are concentric rings of lipid and protein, about 1&nbsp;μm in diameter.

* [[Surfactant protein A|SP-A]] and [[Surfactant protein D|SP-D]] are [[collectin]]s. They confer innate immunity as they have carbohydrate recognition domains that allow them to coat bacteria and viruses promoting phagocytosis by macrophages.<ref>{{cite journal | vauthors = Haagsman HP, Diemel RV | title = Surfactant-associated proteins: functions and structural variation | journal = Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology | volume = 129 | issue = 1 | pages = 91–108 | date = May 2001 | pmid = 11369536 | doi=10.1016/s1095-6433(01)00308-7}}</ref> SP-A is also thought to be involved in a negative feedback mechanism to control the production of surfactant.{{citation needed|date=May 2015}}
* [[Surfactant protein B|SP-B]] and [[Surfactant protein C|SP-C]] are hydrophobic membrane proteins that increase the rate that surfactant spreads over the surface.  SP-B and SP-C are required for the proper biophysical function of the lung. Humans and animals born with a congenital absence of the [[Saposin protein domain|saposin family]] SP-B experience intractable respiratory failure whereas those born lacking SP-C tend to develop progressive interstitial pneumonitis.<ref name=pmid11181967>{{cite journal | vauthors = Weaver TE, Conkright JJ | title = Function of surfactant proteins B and C | journal = Annual Review of Physiology | volume = 63 | pages = 555–78 | year = 2001 | pmid = 11181967 | doi = 10.1146/annurev.physiol.63.1.555 }}</ref>

The SP proteins reduce the critical temperature of DPPC's [[phase transition]] to a value lower than 37&nbsp;°C,<ref>{{cite journal |pmid=10562593 |year=1999 |last1=Hills |first1=B. A. |title=An alternative view of the role(s) of surfactant and the alveolar model |journal=Journal of Applied Physiology |volume=87 |issue=5 |pages=1567–83 |doi=10.1152/jappl.1999.87.5.1567|s2cid=2056951 }}</ref> which improves its adsorption and interface spreading velocity.<ref name="Schuerch_1992">{{cite journal |doi=10.1351/pac199264111745 |title=Pulmonary surfactant: Surface properties and function of alveolar and airway surfactant |journal=Pure and Applied Chemistry |volume=64 |issue=11 |pages=209–20 |year=1992 |last1=Schurch |first1=S. |last2=Lee |first2=Martin |last3=Gehr |first3=Peter |last4=Qanbar |first4=R |last5=Schürch |first5=S |s2cid=97007574 |doi-access=free }}</ref><ref name="Possmayer">{{cite journal |doi=10.1016/S1095-6433(01)00317-8 |pmid=11369545 |title=Surface activity in vitro: Role of surfactant proteins |journal=Comparative Biochemistry and Physiology A |volume=129 |issue=1 |pages=209–20 |year=2001 |last1=Possmayer |first1=Fred |last2=Nag |first2=Kaushik |last3=Rodriguez |first3=Karina |last4=Qanbar |first4=Riad |last5=Schürch |first5=Samuel }}</ref> The compression of the interface causes a phase change of the surfactant molecules to liquid-gel or even gel-solid. The fast adsorption velocity is necessary to maintain the integrity of the gas exchange region of the lungs.

Each SP protein has distinct functions, which act [[synergy|synergistically]] to keep an interface rich in DPPC during lung's expansion and contraction. Changes in the surfactant mixture composition alter the pressure and temperature conditions for phase changes and the phospholipids' crystal shape as well.<ref name="Veldhuizena" /> Only the liquid phase can freely spread on the surface to form a monolayer. Nevertheless, it has been observed that if a lung region is abruptly expanded the floating crystals crack like "[[icebergs]]". Then the SP proteins selectively attract more DPPC to the interface than other phospholipids or cholesterol, whose surfactant properties are worse than DPPC's. The SP also fastens the DPPC on the interface to prevent the DPPC from being squeezed out when the surface area decreases <ref name="Possmayer"/> This also reduces the interface compressibility.<ref name="Schuerch_2001">{{cite journal |doi=10.1016/S1095-6433(01)00316-6 |pmid=11369544 |title=Surface activity in situ, in vivo, and in the captive bubble surfactometer |journal=Comparative Biochemistry and Physiology A |volume=129 |issue=1 |pages=195–207 |year=2001 |last1=Schürch |first1=Samuel |last2=Bachofen |first2=Hans |last3=Possmayer |first3=Fred }}</ref>

==Artificial surfactants==
{{main|Pulmonary surfactant (medication)}}
[[File:Pulmonary surfactant.JPG|thumb|200px|[[Survanta]], surrounded by devices for its application.]]
There are a number of types of pulmonary surfactants available. Ex-situ measurements of [[surface tension]] and [[interfacial rheology]] can help to understand the functionality of pulmonary surfactants.<ref>{{cite journal |last1=Bertsch |first1=Pascal |last2=Bergfreund |first2=Jotam |last3=Windhab |first3=Erich J. |last4=Fischer |first4=Peter |title=Physiological fluid interfaces: Functional microenvironments, drug delivery targets, and first line of defense |journal=Acta Biomaterialia |date=August 2021 |volume=130 |pages=32–53 |doi=10.1016/j.actbio.2021.05.051 |pmid=34077806 |s2cid=235323337 |doi-access=free |hdl=20.500.11850/498803 |hdl-access=free }}</ref>

Synthetic pulmonary surfactants
# [[Colfosceril palmitate]] (Exosurf) - a mixture of DPPC with hexadecanol and tyloxapol added as spreading agents
# [[Pumactant]] (Artificial Lung Expanding Compound or ALEC) - a mixture of DPPC and PG
# [[KL-4]] - composed of DPPC, palmitoyl-oleoyl phosphatidylglycerol, and palmitic acid, combined with a 21 amino acid synthetic peptide that mimics the structural characteristics of SP-B.
# [[Venticute]] - DPPC, PG, palmitic acid and recombinant SP-C
# [[Lucinactant]] - [[dipalmitoylphosphatidylcholine|DPPC]], [[1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol|POPG]], and [[palmitic acid]].

Animal derived surfactants
# [[Beractant]]
## (Alveofact) - extracted from cow lung lavage fluid
## (Survanta) - extracted from minced cow lung with additional DPPC, palmitic acid, and tripalmitin
##(Beraksurf) -extracted from minced calf lung with additional DPPC, palmitic acid, and tripalmitin
# [[Calfactant]] (Infasurf) - extracted from calf lung lavage fluid
# [[Poractant alfa]] (Curosurf) - extracted from material derived from minced pig lung
# [[Ovinactant]] (Varasurf) - extracted from material derived from minced sheep lung

==Surface tension magnitude inside the lung==
Even though the surface tension can be greatly reduced by pulmonary surfactant, this effect will depend on the surfactant's concentration on the interface. The interface concentration has a saturation limit, which depends on temperature and mixture composition. Because during ventilation there is a variation of the lung surface area, the surfactant's interface concentration is not usually at the level of saturation. The surface increases during inspiration, which consequently opens space for new surfactant molecules to be recruited to the interface. Meanwhile, during expiration the surface area decreases at a rate which is always in excess of the rate at which the surfactant molecules are driven from the interface into the water film. Thus, the surfactant density at the air water interface remains high and is relatively preserved throughout expiration, decreasing the surface tension even further. This also explains why the compliance is greater during expiration than during inspiration. {{citation needed|date=May 2015}}

SP molecules contribute to increasing the surfactant interface adsorption kinetics, when the concentration is below the [[Solubility|saturation]] level. They also make [[Van der Waals Forces|weak bonds]] with the surfactant molecules at the interface and hold them longer there when the interface is compressed. Therefore, during ventilation, surface tension is usually lower than at equilibrium. Therefore, the surface tension varies according to the volume of air in the lungs, which protects them from atelectasis at low volumes and tissue damage at high volume levels.<ref name="Schuerch_1992" /><ref name="Veldhuizena" /><ref name="Schuerch_2001" />

{| class="wikitable" style="text-align:center;"
|+ Surface tension values
|-
! Condition
! Tension (mN/m)
|- 
| style="text-align:left;"| Water at 25&nbsp;°C
| 70
|- 
| style="text-align:left;"| Pulmonary surfactant in equilibrium at 36&nbsp;°C
| 25
|- 
| style="text-align:left;"| Healthy lung at 100% of [[Total lung capacity|TLC]]
| 30
|-
| style="text-align:left;"| Healthy lung between 40 and 60% of [[Total lung capacity|TLC]]
| 1~6
|-
| style="text-align:left;"| Healthy lung below 40% of [[Total lung capacity|TLC]]
| <1
|}

==Production and degradation==

Surfactant production in humans begins in [[type II cells]] during the [[Pulmonary alveolus|alveolar sac]] stage of lung development. [[Lamellar bodies]] appear in the cytoplasm at about 20 weeks gestation.<ref>{{Cite web|title=Sinh lý học chu sinh - Nhi khoa|url=https://www.msdmanuals.com/vi/chuy%C3%AAn-gia/nhi-khoa/sinh-l%C3%BD-h%E1%BB%8Dc-chu-sinh/sinh-l%C3%BD-h%E1%BB%8Dc-chu-sinh|access-date=2021-04-23|website=Cẩm nang MSD - Phiên bản dành cho chuyên gia|language=vi}}</ref> These lamellar bodies are secreted by [[exocytosis]] into the [[Epithelial lining fluid|alveolar lining fluid]], where the surfactant forms a meshwork of '''tubular myelin'''<ref name="Young">{{cite journal |last1=Young |first1=SL |last2=Fram |first2=EK |last3=Larson |first3=EW |title=Three-dimensional reconstruction of tubular myelin. |journal=Experimental Lung Research |date=July 1992 |volume=18 |issue=4 |pages=497–504 |doi=10.3109/01902149209064342 |pmid=1516569}}</ref><ref name="Franciosi">{{cite book |last1=Franciosi |first1=L |last2=Govorukhina |first2=N |last3=Ten Hacken |first3=N |last4=Postma |first4=D |last5=Bischoff |first5=R |chapter=Proteomics of Epithelial Lining Fluid Obtained by Bronchoscopic Microprobe Sampling |title=Nanoproteomics |series=Methods in Molecular Biology |date=2011 |volume=790 |pages=17–28 |doi=10.1007/978-1-61779-319-6_2 |pmid=21948403|isbn=978-1-61779-318-9 }}</ref> [[Full term]] infants are estimated to have an alveolar storage pool of approximately 100&nbsp;mg/kg of surfactant, while preterm infants have an estimated 4–5&nbsp;mg/kg at birth.<ref name="Niemarkt Kramer p. ">{{cite journal | last1=Niemarkt | first1=H.J. | last2=Kramer | first2=Boris W. | title=Surfactant for Respiratory Distress Syndrome: New Ideas on a Familiar Drug with Innovative Applications | journal=Neonatology | year=2017 | volume=111 | issue=4 | pages=408–414 | pmid=28538236 | doi=10.1159/000458466 | pmc=5516408 }}</ref>

[[Club cell]]s also produce a component of lung surfactant.<ref>{{Cite book|title=Wheater's functional histology : a text and colour atlas.|last=Young|first=Barbara|others=O'Dowd, Geraldine,, Woodford, Phillip|year=2014|isbn=978-0702047473|edition= Sixth |location=Philadelphia, PA|pages=Ch 12|oclc=861650889}}</ref>

Alveolar surfactant has a half-life of 5 to 10 hours once secreted. It can be both broken down by macrophages and/or reabsorbed into the lamellar structures of type II pneumocytes. Up to 90% of surfactant DPPC (dipalmitoylphosphatidylcholine) is recycled from the alveolar space back into the type II pneumocyte. This process is believed to occur through [[Surfactant protein A|SP-A]] stimulating receptor-mediated, [[clathrin]] dependent [[endocytosis]].<ref>{{cite journal |doi=10.1152/ajplung.00267.2005 |pmid=16169899 |title=Endocytic pathway for surfactant protein a in human macrophages: Binding, clathrin-mediated uptake, and trafficking through the endolysosomal pathway |journal=AJP: Lung Cellular and Molecular Physiology |volume=290 |issue=2 |pages=L334–42 |year=2005 |last1=Crowther |first1=J. E. |last2=Schlesinger |first2=L. S. |s2cid=12759872 }}</ref> The other 10% is taken up by alveolar macrophages and digested.

==Diseases==

*[[Infant respiratory distress syndrome]] (IRDS) is caused by lack of surfactant, commonly seen in premature babies born before 28–32 weeks of gestation. {{citation needed|date=May 2015}}
*[[Congenital surfactant deficiency]]
*[[Pulmonary alveolar proteinosis]]
*[[Surfactant metabolism dysfunction]]

==History==
In late 1920s von Neergaard<ref>{{cite journal |doi=10.1007/bf02621963 |title=Neue Auffassungen über einen Grundbegriff der Atemmechanik |trans-title=New views on a fundamental concept of respiratory mechanics |language=de |journal=Zeitschrift für die Gesamte Experimentelle Medizin |volume=66 |issue=1 |pages=373–94 |year=1929 |last1=Neergaard |first1=K. |s2cid=87610289 }}</ref> identified the function of the pulmonary surfactant in increasing the compliance of the lungs by reducing surface tension. However the significance of his discovery was not understood by the scientific and medical community at that time. He also realized the importance of having low surface tension in lungs of newborn infants. Later, in the middle of the 1950s, Pattle and [[John Allen Clements|Clements]] rediscovered the importance of surfactant and low surface tension in the lungs. At the end of that decade it was discovered that the lack of surfactant caused [[infant respiratory distress syndrome]] (IRDS).<ref>{{Cite journal|last=Avery|first=Mary Ellen|date=1959-05-01|title=Surface Properties in Relation to Atelectasis and Hyaline Membrane Disease|journal=Archives of Pediatrics & Adolescent Medicine|language=en|volume=97|issue=5_PART_I|pages=517–23|doi=10.1001/archpedi.1959.02070010519001|pmid=13649082|s2cid=23200589 |issn=1072-4710}}</ref><ref name="Veldhuizena" >{{cite journal |doi=10.1016/S0925-4439(98)00061-1 |pmid=9813256 |title=The role of lipids in pulmonary surfactant |journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease |volume=1408 |issue=2–3 |pages=90–108 |year=1998 |last1=Veldhuizen |first1=Ruud |last2=Nag |first2=Kaushik |last3=Orgeig |first3=Sandra |last4=Possmayer |first4=Fred |doi-access=free }}</ref>

==References==
{{Reflist}}

==External links==

{{Respiratory physiology}}
{{Membrane proteins}}

{{DEFAULTSORT:Pulmonary Surfactant}}
[[Category:Respiratory physiology]]
[[Category:Integral membrane proteins]]
[[Category:Surfactants]]
[[Category:Pulmonary function testing]]
[[Category:Lipopeptides]]