Surfactant metabolism dysfunction

Last updated
Surfactant metabolism dysfunction
Other namesPrimary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies
Specialty Pulmonology

Surfactant metabolism dysfunction is a condition where pulmonary surfactant is insufficient for adequate respiration. Surface tension at the liquid-air interphase in the alveoli makes the air sacs prone to collapsing post expiration. This is due to the fact that water molecules in the liquid-air surface of alveoli are more attracted to one another than they are to molecules in the air. For sphere-like structures like alveoli, water molecules line the inner walls of the air sacs and stick tightly together through hydrogen bonds. These intermolecular forces put great restraint on the inner walls of the air sac, tighten the surface all together, and unyielding to stretch for inhalation. Thus, without something to alleviate this surface tension, alveoli can collapse and cannot be filled up again. Surfactant is essential mixture that is released into the air-facing surface of inner walls of air sacs to lessen the strength of surface tension. This mixture inserts itself among water molecules and breaks up hydrogen bonds that hold the tension. [1] Multiple lung diseases, like ISD or RDS, in newborns and late-onsets cases have been linked to dysfunction of surfactant metabolism.

Contents

Surfactant is a mixture of 90% phospholipids and 10% other proteins, produced by epithelial type II cells in the alveolar. This mixture is made and packaged into lysosomally- derived structures called lamellar bodies. Lamellar bodies are then secreted into the liquid-air interphase surface of alveolar through membrane fusion initiated by influx of Ca2+. [2] Released pulmonary surfactant acts as a protective layer to prevent alveolar from collapsing due to surface tension. Furthermore, surfactants also contains some innate immune components to defend against pulmonary infections. Surfactant is classified into two types of proteins, hydrophilic proteins that are responsible for innate immune system, and hydrophobic proteins that carry out physical functions of pulmonary surfactant. [3] Surfactant metabolism dysfunction involves mutations or malfunctions of those hydrophobic proteins that lead to ineffective surfactant layer to protect alveolus integrity. [3] SP-B and SP-C are the two hydrophobic surfactant proteins that participate in its physical functions; these proteins are encoded by SFTPB and SFTPC genes on chromosomes 2 and 8 respectively. [4] Thus, mutations on these genes produce incomplete or nonfunctioning SP-B and SP-C proteins and lead to lung diseases.

Both SP-B and SP-C are synthesized in epithelial type II cells as large precursor proteins (proSP-B and proSP-C) and subsequently cleaved by proteolytic enzymes at both amino and carboxyl termini to produce functional mature proteins. [3] proSP-B and proSP-C are first made in the endoplasmic reticulum of epithelial type II cell, they are then translocated through Golgi apparatus to multivesicular bodies for delivery to lamellar bodies. During this transition, proteolytic processing begins to cleave precursor proteins. Once multivescular body reaches the membrane of lamellar body, both membranes fuse together so that processed proteins can be transported into lamellar body, where last steps of maturation for both SP-B and SP-C occur. [4] When lamellar body is ready to be secreted, exocytosis is initiated through influx of Ca2+, and lamellar membrane fuses with plasma membrane to release surfactant phospholipid contents into the surface of the cell. [2] SP-B and SP-C are responsible to carry out adsorption of the lipid monolayer at the liquid-air interphase to prevent post expiration atelectasis. Used surfactant phospholipid materials are taken up into epithelial type II cells by pulmonary macrophages. [2]

Another important protein that contributes to outcome of surfactant metabolism dysfunction is ABCA3, a transmembrane phospholipid transporter in lamellar body. ABCA3 has two ATP binding sites in the cytoplasmic domain to power phospholipid transportation through ATP hydrolysis. ABCA3 is synthesized in endoplasmic reticulum and transported through Golgi apparatus to the membrane of lamellar body. [4] Once inserted into the membrane, ABCA3 can help deliver surfactant lipids into the lumen of lamellar body, and create tightly packed internal environment of surfactant lipids and surfactant proteins. Mutations in ABCA3 cause failure in lamellar body synthesis and result in decreased production of surfactant, along with deficiency of SP-B and SP-C. [3]

Cause

Surfactant metabolism dysfunction describes a group of dysfunctions caused by different mutations in surfactant related genes. Severe deficiency of pulmonary surfactant due to disturbed metabolism of any of these proteins can lead to some form of interstitial lung disease in newborns and adults. These conditions share similar pathophysiology and overlapping phenotypes because surfactant gene products interactively communicate and control one another. [3] Thus, dysfunction of a surfactant protein, or relating protein, generates deficiencies of others.[ citation needed ]

SFTPB mutations

Most disease-causing mutations in SFTPB result in a complete lack of mature SP-B protein 265120. Lung disease is inherited in an autosomal recessive manner, requiring mutations in both alleles. Surfactant produced by infants with SP-B deficiency is abnormal in composition and does not function normally in lowering surface tension.[ citation needed ]

More than 40 different mutations along the length of SFTPB gene have been accounted for in surfactant metabolism dysfunction. SFTPB mutations are inherited in autosomal recessive fashion, loss-of-function mutation on both alleles are required for full expression of disease. About 2/3 or 60%-70% of those accounted disease-causing alleles come from a frameshift mutation, called 121ins2, on exon 4 of SFTPB gene, which also accounts for ~65% of US cases. The rest of the mutated alleles come from nonsense, missense, splice-site mutations, and other possible insertion and deletion mutations throughout the entire gene. [4] These mutations cause total absence or loss-of-function of SP-B and lead to imbalance in surfactant homeostasis. Since SP-B has a major role in surfactant biogenesis and spreading of surfactant and lipid layer, any disruption to existence of SP-B results in ineffective respiration and lethal pulmonary conditions at birth. [5] Pathology manifestation in full-term infant resembles characteristics of newborn with Respiratory Distress Syndrome. [6] Imaging of epithelial type II cells with SP-B deficiency shows immature lamellar bodies without tightly packed membranes, but rather with loose and unorganized membranes. The ratio of phospholipid-protein also decreases with abnormal phospholipids. In addition, surfactant collected from SP-B deficiency epithelial type II cells is not as effective in lowering surface tension and creating film as normal surfactant. [3] Immunohistochemical features of SP-B deficiency show decreased levels of proSP-B and SP-B proteins, along with increased presence of immuno protein SP-A and partially processed intermediate peptides of proSP-C. [4] Appearance of partially processed proSP-C shows significance of mature SP-B in biogenesis and processing of SP-C. Absences of both proSP-B and SP-B proteins are observed in frameshift and nonsense mutations of SFTPB, while low level of proSP-B is detected in missense, in-frame deletionof insertion mutations. However, these mutations prevent proSP-B from fully mature into SP-B, resulting in deficiency of SP-B and surfactant.[ citation needed ]

SFTPC mutations

Familial cases of SP-C dysfunction 610913 are inherited in an autosomal dominant pattern, although the onset and severity of lung disease are highly variable, even within the same family.[ citation needed ]

More than 40 distinct mutation variations in SFTPC gene have also been described in patients. Wild-type SP-C proteins are embedded inside the phospholipid bilayer of epithelial type II cell and function to generate and maintain monolayer of surfactant on alveolar surface. [4] Individuals with mutated SFTPC genes tend to manifest lung diseases in late childhood or adulthood. Mutated alleles are inherited in autosomal dominant fashion, although de novo mutations can also cause sporadic emergence of diseases. The age of onset and severity vary significantly among patients with SFTPC mutations, some only manifest symptoms in fifth or sixth decade. [3] Most of these mutations are missense, but there have been recordings of frameshift, splice-site mutations, together with small insertions or deletions along the carboxyl terminal of SFTPC. Mutations in SFTPC gene are thought to prevent proSP-C peptides from being fully processed into mature SP-C proteins. ProSP-C proteins tend to self-accumulate along the secretory pathway, due to high hydrophobic nature, and may activate cellular destruction response. SFTPC mutations cause proSP-C proteins to aggregate and misfold during secretory process. [3] These folded proteins trigger unfolded protein response (UPR) and cellular apoptosis to get rid of clusters of mutated peptides. Patients with SP-C dysfunction show lack of mature SP-C in epithelial type II cells and up-regulation of UPR. [4] SFTPC mutation with highest occurrence frequency is substitution of threonine for isoleucine in codon 73, termed I73T, found in more than 25% of patients with SP-C related disorders. Staining of proSP-C shows diffuse staining strictly in cytoplasm and accumulation of immunoreactive substances surrounding the nucleus. [4] Evaluation of diseases related to SFTPC mutations show association with chronic parenchymal lung disease.[ citation needed ]

ABCA3 mutations

Mutations in ABCA3 appear to be the most common cause of genetic surfactant dysfunction in humans. [7] [8] [9] The mutations result in a loss of or reduced function of the ABCA3 protein, and are inherited in an autosomal recessive manner 610921.

There are more than 150 different mutations throughout ABCA3 gene with various allelic heterogeneity, making it the biggest class of genetic cause of surfactant dysfunction. Like SP-B deficiency, ABCA3 mutations are inherited in autosomal recessive trait. Mutations of ABCA3 consist of missense, nonsense, frameshift, splice-cite, insertion or deletion. [4] These mutations are classified into two types of ABCA3 mutations, those that preclude normal trafficking of ABCA3 from ER to lamellar membrane, and those that affect ATP-binding ability of ABCA3 needed for phospholipid transportation. [3] Due to its roles in lamellar body biogenesis and maturation of surfactant proteins, epithelial type II cells with altered ABCA3 exhibit premature lamellar bodies and damaged maturation of SP-B/SP-C. Surfactant samples from patients with ABCA3 deficiency do not lower surface tension as effectively. Affected surface tension ability results from incomplete formation of lamellar bodies, due to lack of lipid influx by ABCA3. Immunostaining of SP-B in ABCA3 patients show decreased level of mature SP-B and impaired process of proSP-B to SP-B, thus, confirming why ABCA3 dysfunction leads to severe surfactant metabolism dysfunction. [4]

Diagnosis

Types

Type OMIM GeneLocus
SMDP1 265120 SFTPB 2p12
SMDP2 610913 SPTPC 8p21
SMDP3 610921 ABCA3 16p13
SMDP4 300770 CSF2RA Xp

Non-invasive genetic testing can be used to infer possible interstitial lung disorders caused by surfactant metabolism dysfunction. Although these sequencing tests can take up to several weeks, which may not be so useful in case of acute respiratory problems in newborns. Overlapping phenotypes of surfactant metabolism dysfunction and other interstitial lung diseases make it hard to propose definitive diagnosis for surfactant disorders. Overall testings, family history, external factors, and clinical presentations should all be considered to diagnose surfactant metabolism dysfunction. Testing for surfactant metabolism dysfunction should be considered for newborns with diffuse lung disease or hypoxemia, especially in families with history of neonatal lung diseases or ILD in adults. Neonatal and adult onset lung diseases with unfound causes should also be tested early for surfactant dysfunction. [3] ABCA3 and SP-B dysfunctions manifest in newborns and progress aggressively within the first few months of life, thus, testing for ABCA3 and SP-B disorders should preclude those for SP-C, especially when infants are showing symptoms of ILD or diffuse lung disease. Distinctions between SP-B and ABCA3 are ABCA3 tends to occur in families with neonatal lung disease history, and SP-B testing almost unneeded in older children. [3] Late on-set conditions with inheritance in dominant fashion should infer SP-C dysfunction. Antibodies against proSP-B, proSP-C, SP-B, SP-C, and ABCA3 have been thoroughly developed, which makes detection for these proteins highly accessible and accurate. [4] Immuno staining of each of these type of surfactant dysfunction differs in absence and presence of specific proteins and propeptides, thus immunohistochemisty can help decipher which type of deficiency is being dealt with. In addition, hypothyroidism can cause damaged production of NKX2.1 proteins, which can lead to insufficient transcription of multiple surfactant proteins.[ citation needed ]

Treatment

Neonates with surfactant metabolism dysfunctions, especially those with SP-B disorder, only have lung transplantation as one possible choice of treatment. [3] Children with lung transplant due to surfactant metabolism dysfunction perform on similar level to those with transplant for due to other reasons. [3] Some less severe cases of ABCA3 dysfunctions manifest in late childhood or adult hood are due to missense mutations that result in semi-sufficient levels of active surfactant, while SP-C clinical presentation varies greatly depending on level of penetration of the mutated alleles. [4]

See also

Related Research Articles

<span class="mw-page-title-main">Meconium aspiration syndrome</span> Medical condition affecting newborn infants

Meconium aspiration syndrome (MAS) also known as neonatal aspiration of meconium is a medical condition affecting newborn infants. It describes the spectrum of disorders and pathophysiology of newborns born in meconium-stained amniotic fluid (MSAF) and have meconium within their lungs. Therefore, MAS has a wide range of severity depending on what conditions and complications develop after parturition. Furthermore, the pathophysiology of MAS is multifactorial and extremely complex which is why it is the leading cause of morbidity and mortality in term infants.

<span class="mw-page-title-main">Lung</span> Primary organ of the respiratory system

The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of the heart. Their function in the respiratory system is to extract oxygen from the air and transfer it into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere, in a process of gas exchange. The pleurae, which are thin, smooth, and moist, serve to reduce friction between the lungs and chest wall during breathing, allowing for easy and effortless movements of the lungs.

<span class="mw-page-title-main">Pulmonary alveolus</span> Hollow cavity found in the lungs

A pulmonary alveolus, also known as an air sac or air space, is one of millions of hollow, distensible cup-shaped cavities in the lungs where pulmonary gas exchange takes place. Oxygen is exchanged for carbon dioxide at the blood–air barrier between the alveolar air and the pulmonary capillary. Alveoli make up the functional tissue of the mammalian lungs known as the lung parenchyma, which takes up 90 percent of the total lung volume.

<span class="mw-page-title-main">Pulmonary alveolar proteinosis</span> Medical condition

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder characterized by an abnormal accumulation of surfactant-derived lipoprotein compounds within the alveoli of the lung. The accumulated substances interfere with the normal gas exchange and expansion of the lungs, ultimately leading to difficulty breathing and a predisposition to developing lung infections. The causes of PAP may be grouped into primary, secondary, and congenital causes, although the most common cause is a primary autoimmune condition in an individual.

<span class="mw-page-title-main">Infant respiratory distress syndrome</span> Human disease affecting newborns

Infantile respiratory distress syndrome (IRDS), also called respiratory distress syndrome of newborn, or increasingly surfactant deficiency disorder (SDD), and previously called hyaline membrane disease (HMD), is a syndrome in premature infants caused by developmental insufficiency of pulmonary surfactant production and structural immaturity in the lungs. It can also be a consequence of neonatal infection and can result from a genetic problem with the production of surfactant-associated proteins.

<span class="mw-page-title-main">Interstitial lung disease</span> Group of diseases

Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium and space around the alveoli of the lungs. It concerns alveolar epithelium, pulmonary capillary endothelium, basement membrane, and perivascular and perilymphatic tissues. It may occur when an injury to the lungs triggers an abnormal healing response. Ordinarily, the body generates just the right amount of tissue to repair damage, but in interstitial lung disease, the repair process is disrupted, and the tissue around the air sacs (alveoli) becomes scarred and thickened. This makes it more difficult for oxygen to pass into the bloodstream. The disease presents itself with the following symptoms: shortness of breath, nonproductive coughing, fatigue, and weight loss, which tend to develop slowly, over several months. The average rate of survival for someone with this disease is between three and five years. The term ILD is used to distinguish these diseases from obstructive airways diseases.

<span class="mw-page-title-main">Pulmonary surfactant</span> Complex of phospholipids and proteins

Pulmonary surfactant is a surface-active complex of phospholipids and proteins formed by type II alveolar cells. The proteins and lipids that make up the surfactant have both hydrophilic and hydrophobic regions. By adsorbing to the air-water interface of alveoli, with hydrophilic head groups in the water and the hydrophobic tails facing towards the air, the main lipid component of surfactant, dipalmitoylphosphatidylcholine (DPPC), reduces surface tension.

<span class="mw-page-title-main">Dipalmitoylphosphatidylcholine</span> Chemical compound

Dipalmitoylphosphatidylcholine (DPPC) is a phospholipid (and a lecithin) consisting of two C16 palmitic acid groups attached to a phosphatidylcholine head-group.

<span class="mw-page-title-main">Lamellar bodies</span> Secretory organelles

In cell biology, lamellar bodies are secretory organelles found in type II alveolar cells in the lungs, and in keratinocytes in the skin. They are oblong structures, appearing about 300-400 nm in width and 100-150 nm in length in transmission electron microscopy images. Lamellar bodies in the alveoli of the lungs fuse with the cell membrane and release pulmonary surfactant into the extracellular space.

Collectins (collagen-containing C-type lectins) are a part of the innate immune system. They form a family of collagenous Ca2+-dependent defense lectins, which are found in animals. Collectins are soluble pattern recognition receptors (PRRs). Their function is to bind to oligosaccharide structure or lipids that are on the surface of microorganisms. Like other PRRs they bind pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) of oligosaccharide origin. Binding of collectins to microorganisms may trigger elimination of microorganisms by aggregation, complement activation, opsonization, activation of phagocytosis, or inhibition of microbial growth. Other functions of collectins are modulation of inflammatory, allergic responses, adaptive immune system and clearance of apoptotic cells.

<span class="mw-page-title-main">Surfactant protein D</span> Protein-coding gene in the species Homo sapiens

Surfactant protein D, also known as SP-D, is a lung surfactant protein part of the collagenous family of proteins called collectin. In humans, SP-D is encoded by the SFTPD gene and is part of the innate immune system. Each SP-D subunit is composed of an N-terminal domain, a collagenous region, a nucleating neck region, and a C-terminal lectin domain. Three of these subunits assemble to form a homotrimer, which further assemble into a tetrameric complex.

<span class="mw-page-title-main">Surfactant protein B</span> Protein-coding gene in the species Homo sapiens

Surfactant protein B is an essential lipid-associated protein found in pulmonary surfactant. Without it, the lung would not be able to inflate after a deep breath out. It rearranges lipid molecules in the fluid lining the lung so that tiny air sacs in the lung, called alveoli, can more easily inflate.

<span class="mw-page-title-main">Surfactant protein C</span> Protein-coding gene in the species Homo sapiens

Surfactant protein C (SP-C), is one of the pulmonary surfactant proteins. In humans this is encoded by the SFTPC gene.

<span class="mw-page-title-main">Phosphatidylglycerol</span> Lipid

Phosphatidylglycerol is a glycerophospholipid found in pulmonary surfactant and in the plasma membrane where it directly activates lipid-gated ion channels.

<span class="mw-page-title-main">Surfactant protein A1</span> Protein-coding gene in the species Homo sapiens

Surfactant protein A1(SP-A1), also known as Pulmonary surfactant-associated protein A1(PSP-A) is a protein that in humans is encoded by the SFTPA1 gene.

<span class="mw-page-title-main">ABCA3</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette sub-family A member 3 is a protein that in humans is encoded by the ABCA3 gene.

<span class="mw-page-title-main">Surfactant protein A2</span> Protein-coding gene in the species Homo sapiens

Surfactant protein A2(SP-A2), also known as Pulmonary surfactant-associated protein A2(PSP-A2) is a protein that in humans is encoded by the SFTPA2 gene.

<span class="mw-page-title-main">Diffuse alveolar damage</span> Medical condition

Diffuse alveolar damage (DAD) is a histologic term used to describe specific changes that occur to the structure of the lungs during injury or disease. Most often DAD is described in association with the early stages of acute respiratory distress syndrome (ARDS). It is important to note that DAD can be seen in situations other than ARDS (such as acute interstitial pneumonia) and that ARDS can occur without DAD.

<span class="mw-page-title-main">Pulmonary alveolar microlithiasis</span> Medical condition

Pulmonary alveolar microlithiasis (PAM) is a rare, inherited disorder of lung phosphate balance that is associated with small stone formation in the airspaces of the lung. Mutations in the gene SLC34A2 result in loss of a key sodium, phosphate co-transporter, known to be expressed in distal alveolar type II cells, as well as in the mammary gland, and to a lesser extent in intestine, kidney, skin, prostate and testes. As the disease progresses, the lung fields become progressively more dense (white) on the chest xray, and low oxygen level, lung inflammation and fibrosis, elevated pressures in the lung blood vessels, and respiratory failure ensue, usually in middle age. The clinical course of PAM can be highly variable, with some patients remaining asymptomatic for decades, and others progressing more rapidly. There is no effective treatment, and the mechanisms of stone formation, inflammation and scarring are not known.

References

  1. ↑ Seadler, Benjamin D.; Kaushik, Ravi; Sharma, Sandeep (2020), "Physiology, Alveolar Tension", StatPearls, StatPearls Publishing, PMID   30969647 , retrieved 2020-04-24
  2. 1 2 3 Olmeda, Bárbara; Martínez-Calle, Marta; Pérez-Gil, Jesus (2017-01-01). "Pulmonary surfactant metabolism in the alveolar airspace: Biogenesis, extracellular conversions, recycling". Annals of Anatomy - Anatomischer Anzeiger. 209: 78–92. doi:10.1016/j.aanat.2016.09.008. ISSN   0940-9602. PMID   27773772.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 Gower, W. Adam; Nogee, Lawrence M. (December 2011). "Surfactant Dysfunction". Paediatric Respiratory Reviews. 12 (4): 223–229. doi:10.1016/j.prrv.2011.01.005. ISSN   1526-0542. PMC   3201772 . PMID   22018035.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 Wert, Susan E.; Whitsett, Jeffrey A.; Nogee, Lawrence M. (2009). "Genetic Disorders of Surfactant Dysfunction". Pediatric and Developmental Pathology. 12 (4): 253–274. doi:10.2350/09-01-0586.1. ISSN   1093-5266. PMC   2987676 . PMID   19220077.
  5. ↑ Hawgood, Samuel; Derrick, Matthew; Poulain, Francis (1998-11-19). "Structure and properties of surfactant protein B". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1408 (2): 150–160. doi: 10.1016/S0925-4439(98)00064-7 . ISSN   0925-4439. PMID   9813296.
  6. ↑ McFetridge, Lynne; McMorrow, Aoife; Morrison, Patrick J; Shields, Michael D (January 2009). "Surfactant Metabolism Dysfunction and Childhood Interstitial Lung Disease (chILD)". The Ulster Medical Journal. 78 (1): 7–9. ISSN   0041-6193. PMC   2629012 . PMID   19252722.
  7. ↑ Brasch, F; Griese, M; Tredano, M; Johnen, G; Ochs, M; Rieger, C; Mulugeta, S; Müller, KM; Bahuau, M; Beers, MF (Jul 2004). "Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene". The European Respiratory Journal. 24 (1): 30–9. doi: 10.1183/09031936.04.00000104 . PMID   15293602.
  8. ↑ Shulenin, S; Nogee, LM; Annilo, T; Wert, SE; Whitsett, JA; Dean, M (Mar 25, 2004). "ABCA3 gene mutations in newborns with fatal surfactant deficiency". The New England Journal of Medicine. 350 (13): 1296–303. doi: 10.1056/NEJMoa032178 . PMID   15044640.
  9. ↑ Somaschini, M; Nogee, LM; Sassi, I; Danhaive, O; Presi, S; Boldrini, R; Montrasio, C; Ferrari, M; Wert, SE; Carrera, P (Jun 2007). "Unexplained neonatal respiratory distress due to congenital surfactant deficiency". The Journal of Pediatrics. 150 (6): 649–53, 653.e1. doi:10.1016/j.jpeds.2007.03.008. PMID   17517255.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.