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100BB求助～翻译（截至到11月15日）
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发的篇幅的确比较长，但希望各位虫友能够帮帮忙 声明请您不要拿灵格斯或google翻译的东西给我 提前谢谢好心的人 Inherited defects of surfactant metabolism Hereditary SP-B deficiency. Human SP-B gene (SFTPB) mutations lead to surfactant dysfunction and lethal respiratory distress and were first recognized in term infants with severe respiratory distress after birth [8]. Hereditary SP-B deficiency is inherited as an autosomal recessive condition due to mutation in the SFTPB gene located on chromosome 2. The carrier rate for SFTPB mutation is estimated to be 1 in 1000 [66]. SFTPB mutations include nonsense, missense, frameshift and splicing defects with the most common being a frameshift mutation (121ins2) occurring in exon 4 has accounted for approximately two thirds of the mutant alleles identified to date [66,67]. Mutations in SFTPB typically result in SPB mRNA deficiency or the formation of abnormal SP-B proteins, and ultimately respiratory failure in the newborn period [8]. The normal packaging and routing of SP-C is also disturbed by SP-B deficiency, resulting in immature SP-C in the airspaces [68]. Clinical features suggestive of RDS are observed within a few hours of birth. Radiographic findings include alveolar infiltrates andcollapse, reticular–granular infiltrates and air bronchograms in term infants with no other underlying cause of respiratory failure [8]. A definitive diagnosis is made by the identification of both mutations in alleles of the SFTPB gene. Most infants die within the first month, despite maximal medical therapy. Surfactant replacement is not effective. Lung transplant has provided relief in some of these patients and it has been found that long-term outcomes after lung transplantation for SP-B – deficient infants are similar to those of infants transplanted for other indications [26]. Hereditary SP-C associated disorder. Mutation of the human SP-C gene (SFTPC) resulting in the lack of SP-C are associated with acute and chronic lung disease (CLD) in infants and adults [8]. SP-C deficiency is inherited as an autosomal dominant disorder due to mutation in the SFTPC gene located on the short arm of chromosome 8. The mutation could be familial or de novo [69] and is associated with interstitial lung disease and susceptibility to ARDS following lung injury and infection. The pathophysiology of the lung disease caused by SFTPC mutations may involve multiple mechanisms, including both direct toxicity of abnormal proSP-C, and deficiency of mature SP-C [68]. SP-C is derived from a precursor protein, proSP-C. A misfolding leads to formation and accumulation of abnormal proSP-C in the lung tissue and alveolar spaces which interferes with routing and processing of the proSP-C produced from the normal SFTPC allele [69]. Definitive diagnosis can only be made by the identification of a mutation in the SFTPC gene [8]. Variability in disease severity has been observed with SFTPC mutations, including severe cases resulting in death in early infancy and lung transplantation. The mechanisms for this extreme variability are poorly understood. However, considerable allelic heterogeneity exists but there is no obvious correlation between genotype and disease severity [70]. ABCA3 transporter gene mutation. Mutations in the ABCA3 transporter gene have also been identified as a cause of ARDS in infants, and CLD in older individuals [71]. ABCA3 is a member of the ATPbinding cassette (ABC) transporter family and is highly expressed in the Type II epithelial cells of the lung, predominantly at the limiting membrane of the lamellar bodies [72]. The human ABCA3 gene spans 80 kb of DNA located on the short arm of chromosome 16 and encodes a 1704 amino acid protein [73]. ABCA3 is critical for the proper formation of lamellar bodies and intracellular lipid homeostasis and over 70 ABCA3 mutations including missense, nonsense, splicesite and frameshift mutations have been identified in association with lethal RDS in newborns and chronic respiratory insufficiency [71]. Lung disease from ABCA3 gene mutation is inherited in an autosomal recessive manner with phenotypic heterogeneity ranging from fatal to milder forms [72]. A history of consanguinity and a family history of fatal neonatal RDS support the likelihood of this form of inheritance [8]. For instance, patients with fatal surfactant deficiency carrying a Type I homozygous ABCA3 mutation (W1142X/W1142X, L101P/L101P, or L1553P/ L1553P) or a Type I/Type II compound heterozygous mutation (L982P/G1221S or Ins1518/L1580P) die within the neonatal period while patients carrying a Type II/Type II ABCA3 mutation (E292V/ T1114M or E292V/E690K) exhibit pediatric forms of interstitial lung disease suggesting that the Type II/Type II ABCA3 mutation produces a milder phenotype [71,72]. Mutations in full-term newborns are associated with a defective assembly of lamellar bodies, an abnormal staining pattern of Type II pneumocytes for SP-B, and fatal surfactant deficiency [71]. Newborn infants present with grunting, chest retractions and cyanosis followed by rapidly progressive respiratory failure refractory to ventilation and ECMO, and have also presented as persistent pulmonary hypertension of the newborn [74]. Pulmonary opacification, reticular–granular infiltrates and air bronchograms are seen on chest radiographs. ABCA3 (/) mice have grossly reduced surfactant phosphatidyl glycerol levels and die of respiratory failure soon after birth [75]. There are no known treatments for lung disease resulting from this mutation and the infants die within the first month of life despite maximal medical therapy. Summary An understanding of the complex metabolic process involving phospholipids and surfactant proteins is the key in the management of respiratory failure secondary to defects in surfactant metabolism. The combined use of prenatal corticosteroids and postnatal surfactant replacement therapy can be credited with a dramatic improvement in the outcome of patients with RDS [45]. Lung transplantation has been successful in treating infants with inherited SP-B deficiency and has also afforded the opportunity to investigate surfactant composition and function. Additional experience with infants with inherited mutations in the SP-C gene will help predict the natural history and provide more informed decision-making about lung transplant in these patients [36]. Whole lung lavage is currently the mainstay of treatment in pulmonary alveolar proteinosis [59] and further studies to ascertain the role of SP-B and GM-CSF will help in advancing further ground breaking therapy for this disease. Gene therapy could overcome the limitations of surfactant replacement therapy in inherited defects of surfactant metabolism. |
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