Lung Surfactant, Respiratory Failure, and Genes
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《新英格兰医药杂志》
After the first observation of surfactant deficiency in infants who were dying of the respiratory distress syndrome (also known as hyaline membrane disease), a series of investigations led to effective therapies, including surfactant therapy given at birth. These therapies, in turn, have led to a dramatic decrease in mortality associated with the respiratory distress syndrome, from nearly 100 percent to less than 10 percent. Most infants who die from the syndrome are preterm. Surfactant therapy is usually not required beyond the first day of life, because the turnover of surfactant is slow in newborns, and the rapid differentiation of alveolar tissue leads to sufficient endogenous secretion within days after birth in most cases. However, there are still some cases of the respiratory distress syndrome that are resistant to treatment, and an understanding of what causes them may lead to strategies for prevention and new therapies.
The synthesis, storage, secretion, recycling, and catabolism of alveolar surfactant take place in alveolar type II cells (see Figure), which are characterized by lamellar bodies — organelles containing concentric, onion-like layers of surfactant. Alveolar macrophages also mediate the catabolism of surfactant. In the alveolar lining, surfactant released by lamellar bodies (when the limiting membrane fuses with the cell membrane) is transformed into aggregates made up of tubular myelin that can both enter the air–water interface exceptionally quickly by means of adsorption and nearly eliminate the surface tension of that interface. Low surface tension in the lining of the tiny spherical air spaces prevents generalized atelectasis (collapse) and its devastating consequences. Ninety percent of the surfactant complex consists of specific lipids enriched with dipalmitoyl phosphatidylcholines that form the film at the air–water interface. Of the four surfactant proteins A, B, C, and D, three (hydrophobic transmembrane surfactant proteins B and C and collectin surfactant protein A) bind to surfactant lipids.
Figure. Lung Surfactant and the Lamellar Body.
The composition of lung surfactant is critical to lung function, and the subcellular lamellar body of the type II alveolar cell has a major role in maintaining the composition of surfactant. The distribution of ATP-binding cassette (ABC) transporter A3 (ABCA3) is shown in red. It is possible that ABCA3 targets surfactant-containing vesicles to the lamellar bodies. The lamellar body is formed through the fusion of several multivesicular bodies, and its lipid bilayers are converted to tubular myelin as they are turned out into the alveolar space. Surfactant protein A, secreted primarily by a constitutive pathway that does not involve the lamellar body, is required for the formation of tubular myelin. Surfactant aggregate, such as tubular myelin, is the precursor of surfactant at the air–water interface (inset). Cationic transmembrane proteins (surfactant protein B or surfactant protein C or both ) together with anionic phospholipids (phosphatidylglycerol or phosphatidylinositol or both ) facilitate the entry of dipalmitoyl phosphatidylcholines (blue) into the monolayer at the interface, maintaining a low surface tension. During tidal breathing, tubular myelin surfactant is converted to smaller aggregates that are taken up by type II cells and alveolar macrophages. Arrows depict the direction of surfactant flux.
Hereditary respiratory failure in term infants has been attributed to mutations in the genes encoding surfactant protein B (SP-B) and surfactant protein C (SP-C). In this issue of the Journal, Shulenin et al. (pages 1296 –1303) describe a third genetic cause in 16 cases: recessive mutations in the gene encoding the ATP-binding cassette (ABC) transporter A3 (ABCA3).1 Close examination of alveolar tissue from four patients uncovered small, abnormal lamellar bodies, leading the authors to propose that ABCA3 is critical to the formation of lamellar bodies.
Although the molecular action of ABCA3 is unclear, we know about the biologic behavior of other ABCA proteins, which may be relevant to that of ABCA3. The ABCA subfamily consists of 12 transporter genes, some of which are known to mediate ATP-driven lipid transport across a lipid-bilayer membrane. Tangier disease, a multiorgan hyperlipidemia syndrome, is caused by a loss-of-function mutation in the ABCA1 gene; ABCA1 controls the extrusion of the membrane lipid toward extracellular acceptors, the apolipoproteins. Stargardt's disease, which affects the retina, is caused by loss-of-function mutations in the ABCA4 gene. This protein serves as a "flippase"; it catalyzes a 180° rotation of a specific phospholipid derivative and simultaneously moves it from the inner leaflet of the lipid bilayer to the outer leaflet within the disk membrane of the rod cell. ABCA3 is found in the outer limiting membrane of lamellar bodies, multivesicular bodies, and segments of luminal plasma membrane of alveolar type II cells. This pattern of expression, together with the known functions of ABCA1 and ABCA4, is consistent with the possibility that ABCA3 mediates the targeting of surfactant-containing vesicles to the lamellar bodies.
The phenotype of the patients characterized by Shulenin et al. resembles that of patients with mutations of the SP-B gene: both groups of patients have fatal respiratory failure and highly abnormal lamellar bodies, and in both, histologic analysis reveals neonatal alveolar proteinosis.2 In contrast, the phenotypes of patients with a mutation of the SP-C gene are varied: some have mild respiratory symptoms, whereas others have severe respiratory failure. Histologic analysis reveals interstitial lung disease.2 In fatal respiratory failure due to the absence of surfactant protein B, surfactant protein C precursor protein is not cleaved to form mature surfactant protein C, so the precursor protein accumulates in the alveolar space. A dominant negative mutation of SP-C, on the other hand, may result in the aggregation of misfolded surfactant protein C precursor protein and subsequent injury and inflammation.
The lungs of the patients studied by Shulenin et al. showed hyperplasia of alveolar macrophages and alveolar type II cells, as well as indications of desquamative interstitial pneumonitis or alveolar proteinosis. The abnormally small, densely packed lamellar bodies suggest the presence of abnormal surfactant that probably does not have the near-zero surface tension required for alveolar stability. Further study to determine the distribution of surfactant and other membrane components in bronchoalveolar lavage fluid and in lung compartments — together with experimental studies using mouse models — will contribute to a more accurate picture of ABCA3 deficiency.
Although heritable cases of the respiratory distress syndrome can be prevented through genetic counseling and prenatal diagnosis, we may not be aware of all the genes that can fatally affect the surfactant system. Nor do we yet know the proportion of cases of the respiratory distress syndrome that are caused by a mutation of ABCA3, which may be similar to the proportion caused by a mutation of the SP-B gene (in the range of 1 case in 1 million newborns). It is also possible that the common allelic variants of the genes encoding the surfactant proteins, together with environmental factors, influence susceptibility to serious respiratory disease.3
Source Information
From the Biocenter Oulu and the Department of Pediatrics, University of Oulu — both in Oulu, Finland.
References
Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 2004;350:1296-1303.
Whitsett JA, Weaver TE. Hydrophobic surfactant proteins in lung function and disease. N Engl J Med 2002;347:2141-2148.
Haataja R, Hallman M. Surfactant proteins as genetic determinants of multifactorial pulmonary diseases. Ann Med 2002;34:324-333.(Mikko Hallman, M.D., Ph.D)
The synthesis, storage, secretion, recycling, and catabolism of alveolar surfactant take place in alveolar type II cells (see Figure), which are characterized by lamellar bodies — organelles containing concentric, onion-like layers of surfactant. Alveolar macrophages also mediate the catabolism of surfactant. In the alveolar lining, surfactant released by lamellar bodies (when the limiting membrane fuses with the cell membrane) is transformed into aggregates made up of tubular myelin that can both enter the air–water interface exceptionally quickly by means of adsorption and nearly eliminate the surface tension of that interface. Low surface tension in the lining of the tiny spherical air spaces prevents generalized atelectasis (collapse) and its devastating consequences. Ninety percent of the surfactant complex consists of specific lipids enriched with dipalmitoyl phosphatidylcholines that form the film at the air–water interface. Of the four surfactant proteins A, B, C, and D, three (hydrophobic transmembrane surfactant proteins B and C and collectin surfactant protein A) bind to surfactant lipids.
Figure. Lung Surfactant and the Lamellar Body.
The composition of lung surfactant is critical to lung function, and the subcellular lamellar body of the type II alveolar cell has a major role in maintaining the composition of surfactant. The distribution of ATP-binding cassette (ABC) transporter A3 (ABCA3) is shown in red. It is possible that ABCA3 targets surfactant-containing vesicles to the lamellar bodies. The lamellar body is formed through the fusion of several multivesicular bodies, and its lipid bilayers are converted to tubular myelin as they are turned out into the alveolar space. Surfactant protein A, secreted primarily by a constitutive pathway that does not involve the lamellar body, is required for the formation of tubular myelin. Surfactant aggregate, such as tubular myelin, is the precursor of surfactant at the air–water interface (inset). Cationic transmembrane proteins (surfactant protein B or surfactant protein C or both ) together with anionic phospholipids (phosphatidylglycerol or phosphatidylinositol or both ) facilitate the entry of dipalmitoyl phosphatidylcholines (blue) into the monolayer at the interface, maintaining a low surface tension. During tidal breathing, tubular myelin surfactant is converted to smaller aggregates that are taken up by type II cells and alveolar macrophages. Arrows depict the direction of surfactant flux.
Hereditary respiratory failure in term infants has been attributed to mutations in the genes encoding surfactant protein B (SP-B) and surfactant protein C (SP-C). In this issue of the Journal, Shulenin et al. (pages 1296 –1303) describe a third genetic cause in 16 cases: recessive mutations in the gene encoding the ATP-binding cassette (ABC) transporter A3 (ABCA3).1 Close examination of alveolar tissue from four patients uncovered small, abnormal lamellar bodies, leading the authors to propose that ABCA3 is critical to the formation of lamellar bodies.
Although the molecular action of ABCA3 is unclear, we know about the biologic behavior of other ABCA proteins, which may be relevant to that of ABCA3. The ABCA subfamily consists of 12 transporter genes, some of which are known to mediate ATP-driven lipid transport across a lipid-bilayer membrane. Tangier disease, a multiorgan hyperlipidemia syndrome, is caused by a loss-of-function mutation in the ABCA1 gene; ABCA1 controls the extrusion of the membrane lipid toward extracellular acceptors, the apolipoproteins. Stargardt's disease, which affects the retina, is caused by loss-of-function mutations in the ABCA4 gene. This protein serves as a "flippase"; it catalyzes a 180° rotation of a specific phospholipid derivative and simultaneously moves it from the inner leaflet of the lipid bilayer to the outer leaflet within the disk membrane of the rod cell. ABCA3 is found in the outer limiting membrane of lamellar bodies, multivesicular bodies, and segments of luminal plasma membrane of alveolar type II cells. This pattern of expression, together with the known functions of ABCA1 and ABCA4, is consistent with the possibility that ABCA3 mediates the targeting of surfactant-containing vesicles to the lamellar bodies.
The phenotype of the patients characterized by Shulenin et al. resembles that of patients with mutations of the SP-B gene: both groups of patients have fatal respiratory failure and highly abnormal lamellar bodies, and in both, histologic analysis reveals neonatal alveolar proteinosis.2 In contrast, the phenotypes of patients with a mutation of the SP-C gene are varied: some have mild respiratory symptoms, whereas others have severe respiratory failure. Histologic analysis reveals interstitial lung disease.2 In fatal respiratory failure due to the absence of surfactant protein B, surfactant protein C precursor protein is not cleaved to form mature surfactant protein C, so the precursor protein accumulates in the alveolar space. A dominant negative mutation of SP-C, on the other hand, may result in the aggregation of misfolded surfactant protein C precursor protein and subsequent injury and inflammation.
The lungs of the patients studied by Shulenin et al. showed hyperplasia of alveolar macrophages and alveolar type II cells, as well as indications of desquamative interstitial pneumonitis or alveolar proteinosis. The abnormally small, densely packed lamellar bodies suggest the presence of abnormal surfactant that probably does not have the near-zero surface tension required for alveolar stability. Further study to determine the distribution of surfactant and other membrane components in bronchoalveolar lavage fluid and in lung compartments — together with experimental studies using mouse models — will contribute to a more accurate picture of ABCA3 deficiency.
Although heritable cases of the respiratory distress syndrome can be prevented through genetic counseling and prenatal diagnosis, we may not be aware of all the genes that can fatally affect the surfactant system. Nor do we yet know the proportion of cases of the respiratory distress syndrome that are caused by a mutation of ABCA3, which may be similar to the proportion caused by a mutation of the SP-B gene (in the range of 1 case in 1 million newborns). It is also possible that the common allelic variants of the genes encoding the surfactant proteins, together with environmental factors, influence susceptibility to serious respiratory disease.3
Source Information
From the Biocenter Oulu and the Department of Pediatrics, University of Oulu — both in Oulu, Finland.
References
Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 2004;350:1296-1303.
Whitsett JA, Weaver TE. Hydrophobic surfactant proteins in lung function and disease. N Engl J Med 2002;347:2141-2148.
Haataja R, Hallman M. Surfactant proteins as genetic determinants of multifactorial pulmonary diseases. Ann Med 2002;34:324-333.(Mikko Hallman, M.D., Ph.D)