Editing Meconium aspiration syndrome (section)

==Pathophysiology==
As MAS describes a spectrum of disorders of newborns born through MSAF, without any congenital respiratory disorders or other underlying pathology, there are numerous hypothesised mechanisms and causes for the onset of this syndrome. Long-term consequences may arise from these disorders, for example, infants that develop MAS have higher rates of developing neurodevelopmental defects due to poor respiration.<ref>{{Cite journal|last1=Beligere|first1=N|last2=Rao|first2=R|date=2008|title=Neurodevelopmental Outcome of Infants with Meconium Aspiration Syndrome: Report of a Study and Literature Review|journal=Journal of Perinatology|volume=28|pages=S93–S101|doi=10.1038/jp.2008.154|pmid=19057618|doi-access=free}}</ref>

=== Airway obstruction ===
In the first 15 minutes of meconium aspiration, there is obstruction of larger airways which causes increased lung resistance, decreased [[lung compliance]], acute [[hypoxemia]], [[hypercapnia]], [[atelectasis]] and [[respiratory acidosis]]. After 60 minutes of exposure, the meconium travels further down into the smaller airways. Once within the terminal bronchioles and alveoli, the meconium triggers inflammation, [[pulmonary edema]], [[vasoconstriction]], [[bronchoconstriction]], collapse of airways and inactivation of [[surfactant]].<ref name=":13" /><ref name=":7" />

=== Foetal hypoxia ===
The lung areas which do not or only partially participate in [[ventilation (physiology)|ventilation]], because of obstruction and/or destruction, will become hypoxic and an inflammatory response may consequently occur. Partial obstruction will lead to air trapping and [[hyperinflation]] of certain lung areas and [[pneumothorax]] may follow. Chronic hypoxia will lead to an increase in pulmonary vascular smooth muscle tone and [[persistent pulmonary hypertension]] causing respiratory and circulatory failure.<ref name=":0" />

=== Infection ===
Microorganisms, most commonly [[Gram-negative bacteria|Gram-negative]] rods, and [[endotoxins]] are found in samples of MSAF at a higher rate than in clear amniotic fluid, for example 46.9% of patients with MSAF also had endotoxins present. A microbial invasion of the amniotic cavity (MIAC) is more common in patients with MSAF and this could ultimately lead to an intra-amniotic inflammatory response. MIAC is associated with high concentrations of [[cytokine]]s (such as [[Interleukin 6|IL-6]]), [[chemokine]]s (such as [[Interleukin 8|IL-8]] and [[monocyte chemoattractant protein-1]]), [[Complement system|complement]], [[Phospholipase A2|phospholipase A<sub>2</sub>]] and matrix-degrading enzymes. Therefore, these aforementioned mediators within the amniotic fluid during MIAC and intra-amniotic infection could, when aspirated ''in'' ''utero'', induce lung inflammation within the foetus.<ref>{{Cite journal|last1=Romero|first1=R|last2=Yoon|first2=BH|last3=Chaemsaithong|first3=P|last4=Cortez|first4=J|last5=Park|first5=CW|last6=Behnke|first6=RGE|last7=Hassan|first7=SS|last8=Chaiworapongsa|first8=T|last9=Yeo|first9=L|date=2014|title=Bacteria and Endotoxin in Meconium-Stained Amniotic Fluid at Term: Could Intra-amniotic Infection Cause Meconium Passage?|journal=The Journal of Maternal-Fetal and Neonatal Medicine|volume=27|issue=8|pages=775–788|doi=10.3109/14767058.2013.844124|pmc=5881914|pmid=24028637}}</ref>

=== Pulmonary inflammation ===
Meconium has a complex chemical composition, so it is difficult to identify a single agent responsible for the several diseases that arise. As meconium is stored inside the [[intestines]], and is partly unexposed to the [[immune system]], when it becomes aspirated the [[innate immune system]] recognises as a foreign and dangerous substance. The immune system, which is present at birth, responds within minutes with a low specificity and no memory in order to try to eliminate [[Microorganism|microbes]]. Meconium perhaps leads to [[chemical pneumonitis]] as it is a potent activator of inflammatory mediators which include [[cytokine]]s, [[Complement system|complement]], [[prostaglandin]]s and [[reactive oxygen species]].<ref name=":4" />

Meconium is a source of pro-inflammatory [[cytokine]]s, including [[tumour necrosis factor]] (TNF) and [[interleukin]]s ([[Interleukin-1 family|IL-1]], [[Interleukin 6|IL-6]], [[Interleukin 8|IL-8]]), and mediators produced by [[neutrophil]]s, [[macrophage]]s and epithelial cells that may injure the lung tissue directly or indirectly. For example, [[proteolytic enzymes]] are released from neutrophilic granules and these may damage the lung membrane and surfactant proteins. Additionally, activated [[leukocytes]] and cytokines generate [[Reactive nitrogen species|reactive nitrogen]] and [[Reactive oxygen species|oxygen species]] which have [[Cytotoxicity|cytotoxic]] effects. [[Oxidative stress]] results in [[vasoconstriction]], [[bronchoconstriction]], [[platelet aggregation]] and accelerated cellular [[apoptosis]].<ref name=":7">{{Cite journal|last1=Mokra|first1=D|last2=Mokry|first2=J|last3=Tonhajzerova|first3=I|date=2013|title=Anti-Inflammatory Treatment of Meconium Aspiration Syndrome: Benefits and Risks|journal=Respiratory Physiology and Neurobiology|volume=187|issue=1|pages=52–57|doi=10.1016/j.resp.2013.02.025|pmid=23466955|s2cid=41008280}}</ref> Recently, it has been hypothesised that meconium is a potent activator of [[toll-like receptor]] (TLRs) and [[Complement system|complement]], key mediators in inflammation, and may thus contribute to the inflammatory response in MAS.<ref name=":0" /><ref name=":4" />

Meconium contains high amounts of [[Phospholipase A2|phospholipase A<sub>2</sub>]] (PLA<sub>2</sub>), a potent proinflammatory enzyme, which may directly (or through the stimulation of [[arachidonic acid]]) lead to surfactant dysfunction, lung epithelium destruction, tissue [[necrosis]] and an increase in [[apoptosis]].<ref name=":0" /><ref name=":7" /> Meconium can also activate the [[coagulation cascade]], production of [[platelet-activating factor]] (PAF) and other vasoactive substances that may lead to destruction of capillary [[endothelium]] and [[basement membrane]]s. Injury to the alveolocapillary membrane results in leakage of liquid, plasma proteins, and cells into the [[interstitium]] and [[Pulmonary alveolus|alveolar]] spaces.<ref name=":7" />

=== Surfactant inactivation ===
[[Surfactant]] is synthesised by [[Alveolar cells|type II alveolar cells]] and is made of a complex of [[phospholipid]]s, proteins and [[saccharides]]. It functions to lower [[surface tension]] (to allow for lung expansion during [[Inhalation|inspiration]]), stabilise [[Pulmonary alveolus|alveoli]] at the end of [[Breathing|expiration]] (to prevent alveolar collapse) and prevents lung [[Edema|oedema]]. Surfactant also contributes to lung protection and defence as it is also an anti-inflammatory agent. Surfactant enhances the removal of inhaled particles and [[Senescence|senescent]] cells away from the alveolar structure.<ref>{{Cite journal|last1=Dargaville|first1=PA|last2=Mills|first2=JF|date=2005|title=Surfactant therapy for meconium aspiration syndrome: current status|journal=Drugs|volume=65|issue=18|pages=2569–2591|doi=10.2165/00003495-200565180-00003|pmid=16392874 |s2cid=46969843 |doi-access=free}}</ref>

The extent of surfactant inhibition depends on both the concentration of surfactant and meconium. If the surfactant concentration is low, even very highly diluted meconium can inhibit surfactant function whereas, in high surfactant concentrations, the effects of meconium are limited. Meconium may impact surfactant mechanisms by preventing surfactant from spreading over the alveolar surface, decreasing the concentration of surfactant proteins ([[Surfactant protein A|SP-A]] and [[Surfactant protein B|SP-B]]), and by changing the viscosity and structure of surfactant.<ref name=":13">{{Cite journal|last1=Mokra|first1=D|last2=Calkovska|first2=A|date=2013|title=How to Overcome Surfactant Dysfunction in Meconium Aspiration Syndrome|journal=Respiratory Physiology and Neurobiology|volume=187|issue=1|pages=58–63|doi=10.1016/j.resp.2013.02.030|pmid=23473924|s2cid=20533996}}</ref> Several morphological changes occur after meconium exposure, the most notable being the detachment of airway epithelium from [[Basement membrane|stroma]] and the shedding of [[Epithelium|epithelial cells]] into the airway. These indicate a direct detrimental effect on lung alveolar cells because of the introduction of meconium into the lungs.<ref name=":0" />

=== Persistent Pulmonary Hypertension ===
[[Persistent pulmonary hypertension]] (PPHN) is the failure of the foetal circulation to adapt to extra-uterine conditions after birth. PPHN is associated with various respiratory diseases, including MAS (as 15-20% of infants with MAS develop PPHN), but also [[pneumonia]] and [[sepsis]]. A combination of [[Hypoxia (medical)|hypoxia]], pulmonary [[vasoconstriction]] and [[Breathing|ventilation]]/[[perfusion]] mismatch can trigger PPHN, depending on the concentration of meconium within the [[respiratory tract]].<ref>{{Cite journal|last=Brooke-Vincent|first=F|date=2015|title=Meconium Aspiration Syndrome and Persistent Pulmonary Hypertension of the Newborn|journal=Journal of Neonatal Nursing|volume=21|issue=4|pages=161–167|doi=10.1016/j.jnn.2015.05.002}}</ref><ref name=":6" /> PPHN in newborns is the leading cause of death in MAS.<ref name=":4" />

=== Apoptosis ===
[[Apoptosis]] is an important mechanism in the clearance of injured cells and in tissue repair, however too much apoptosis may cause harm, such as acute lung injury. Meconium induces apoptosis and [[DNA]] cleavage of lung airway epithelial cells, this is detected by the presence of fragmented DNA within the airways and in alveolar epithelial nuclei. Meconium induces an inflammatory reaction within the lungs as there is an increase of [[Autophagy|autophagocytic]] cells and levels of [[caspase 3]] after exposure. After 8 hours of meconium exposure, in rabbit foetuses, the total amount of apoptotic cells is 54%.<ref>{{Cite journal|last1=Zagariya|first1=A|last2=Bhat|first2=R|last3=Chari|first3=G|last4=Uhal|first4=B|last5=Navale|first5=S|last6=Vidyasagar|first6=D|date=2005|title=Apoptosis of Airway Epithelial Cells in Response to Meconium|journal=Life Sciences|volume=76|issue=16|pages=1849–1858|doi=10.1016/j.lfs.2004.10.033|pmid=15698862}}</ref> Therefore, the majority of meconium-induced lung damage may be due to the apoptosis of lung epithelium.<ref name=":0" />