Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A pressure-driven captive bubble surfactometer was used to determine the role of surfactant proteins in refinement of the surface film. The advantage of this apparatus is that surface films can be spread at the interface of an air bubble with a different lipid/protein composition than the subphase vesicles. Using different combinations of subphase vesicles and spread surface films a clear correlation between dipalmitoylphosphatidylcholine (DPPC) content and minimum surface tension was observed. Spread phospholipid films containing 50% DPPC over a subphase containing 50% DPPC vesicles did not form stable surface films with a low minimum surface tension. Addition of surfactant protein B (SP-B) to the surface film led to a progressive decrease in minimum surface tension toward 1 mN/m upon cycling, indicating an enrichment in DPPC. Surfactant protein C (SP-C) had no such detectable refining effect on the film. Surfactant protein A (SP-A) had a positive effect on refinement when it was present in the subphase. However, this effect was only observed when SP-A was combined with SP-B and incubated with subphase vesicles before addition to the air bubble containing sample chamber. Comparison of spread films with adsorbed films indicated that refinement induced by SP-B occurs by selective removal of non-DPPC lipids upon cycling. SP-A, combined with SP-B, induces a selective adsorption of DPPC from subphase vesicles into the surface film. This is achieved by formation of large lipid structures which might resemble tubular myelin.
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PMID:The role of surfactant proteins in DPPC enrichment of surface films. 1110 21

The acute respiratory distress syndrome (ARDS) is a clinical syndrome with primarily supportive management options. Despite extensive basic and clinical investigations, multiple pharmacological and nonpharmacological modalities have been unsuccessful in decreasing mortality. Nonetheless, these efforts have substantially heightened our understanding of ARDS pathophysiology. Investigators continue to create new and more complex therapeutic strategies that may have significant clinical impact. Several pharmacological agents for ARDS are in development and have shown either great promise or are at most, under phase II evaluation. The order in which therapeutic options are presented in this review highlights therapeutic options other than the anti-inflammatory approach. In addition to the anti-inflammatory category, vasodilators, surfactant therapy, immunonutrition and partial liquid ventilation are all being evaluated. Within the anti-inflammatory category. new mechanistic approaches include the 'anti-inflammatory nature' of interleukin-10, the inhibitory aspects of lysophosphatidic acid on endothelial cell permeability, and the use of recombinant human anti-coagulant proteins (activated protein C and tissue factor pathway inhibitor) to reduce the inflammatory cycle that contributes to microvascular thrombi. Previous work with surfactant in ARDS had its limitations, however, these trials were of sufficient success to spawn 2 new synthetic compounds. These new synthetic surfactants incorporate mixtures of phosphatidylcholine and phosphatidylglycerol (the key phospholipids within endogenous surfactant) and either recombinant surfactant protein C or an analogue of surfactant protein B. Recently, the ARDS Network's low tidal volume study has broken the cycle of decades of negative ARDS trials and demonstrated an improvement in mortality. Through better mechanistic approach and study design, investigator compliance with exclusion criteria, and better understanding of the complexities of patient management, the next pharmacological ARDS trials will hopefully be successful and lead to further reductions in patient mortality.
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PMID:Acute respiratory distress syndrome: pharmacological treatment options in development. 1143 47

Sclerosing hemangioma (PSH) is a rare pulmonary tumor, in which two types of tumor cells could be histologically discerned--surface and stromal tumor cells. Nine tumor-tissue specimens from six female Japanese patients were studied, focusing on the distribution of several transcription factors related to lung epithelial development and surfactant proteins and comparing the ultrastructural features of the tumor cells. The immunohistochemical analysis revealed that the surfactant proteins of surfactant apoprotein A, surfactant protein B, and prosurfactant protein C were distributed in many of the surface-lining cells and in a small number of stromal-tumor cells. In addition, the nuclei of the tumor cells stained positive for thyroid transcription factor 1 (TTF)-1, hepatocyte nuclear factor (HNF)-3 alpha, and HNF-3 beta. In situ hybridization staining for TTF-1 showed similar positive signals. Ultrastructurally, two types of tumor cells showed similar features, but stromal tumor cells lost the definitive apico-lateral differentiation compared with the surface tumor cells and showed restricted surface differentiation between the adjacent tumor cells, forming small lumina accompanied by microvilli and occasional multi-vesicle or multi-lamellar bodies. Conclusively, the real tumoral population being undifferentiated stromal cells, the lining cells are fully differentiated type-II pneumonocytes. PSH is a proliferation of rather fetal type-II pneumonocytes (pneumocytoma or pneumoblastoma?).
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PMID:Type-II pneumocyte differentiation in pulmonary sclerosing hemangioma: ultrastructural differentiation and immunohistochemical distribution of lineage-specific transcription factors (TTF-1, HNF-3 alpha, and HNF-3 beta) and surfactant proteins. 1513 14

Although genetic factors are assumed to have a role in the etiology of respiratory distress syndrome (RDS), specific genes underlying this susceptibility are incompletely known. The most promising candidates are the genes coding for the lung-specific protein components of the surfactant. In congenital absence of surfactant protein A in mice, lung mechanics or surfactant homeostasis is normal. However, there is an increased susceptibility to infections. The major surfactant protein A alleles, 6A(2) and 1A(0), are the general high-risk RDS alleles, while the allele 6A(3) carries a decreased risk of RDS. The allele 6A(6) is also over-represented in infants with bronchopulmonary dysplasia. To date, no human infants who lack surfactant protein A have been identified, and the human respiratory phenotype associated with the 1A(0) allele has been demonstrated to be variable, therefore, surfactant protein A polymorphisms are not currently useful for estimation of individual risk of having an affected infant. Surfactant protein B (SP-B) plays an essential role in the structure of tubular myelin. Mutations resulting in an absence of surfactant protein B have been identified. They cause a recessively inherited, progressive respiratory disease. More than 27 loss of function mutations have been identified in the surfactant protein B gene that result in lethal neonatal respiratory failure. Of the several known common variants of the surfactant protein B gene, the most common mutation is 121ins22 that accounts for 60-70% of the mutant cases. Although the frequency of the 121ins2 mutation is rare, the consistent phenotype is exhibited by infants with a homozygous genotype. The clinical presentation in infants homozygous for the 121ins2 mutation is full-term infants who develop respiratory distress within the first 12-24 hours of life. Surfactant replacement therapy fails to reverse this outcome, and without lung transplantation, they expire within the first 1-6 months of life. Surfactant protein B gene mutations may also result in milder phenotypes. These mutations resulting in reduced synthesis of SP-B appear to be family-specific and result in respiratory distress, but sometimes with more gradually progressive or chronic respiratory failure. Surfactant protein C plays a role in the stabilization of surfactant and may also have a role in the intracellular processing of the surfactant complex. Surfactant protein B is important in the intracellular processing and production of surfactant protein C. Although surfactant protein C-deficient mice are viable and survive to adulthood without obvious pulmonary abnormalities, their lung have reduced viscoelasticty. Human respiratory disease in the neonatal period caused by loss-of-function mutations in the surfactant protein C gene has not been identified. However, an autosomal dominant inherited mutation at the surfactant protein C gene causes chronic interstitial lung disease. Surfactant protein D is a member of the collectin family like surfactant protein A, therefore it opsonizes pathogens and enhances their phagocytosis by alveolar macrophages and neutrophils. Unlike surfactant protein A, it does not contribute to lowering surface tension. Surfactant protein D-deficient mice have no respiratory abnormalities at birth, but it causes development of emphysema and predisposition to specific infections. No human infant or child with respiratory distress and mutation in the surfactant protein D gene has been identified.
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PMID:Inherited disorders of neonatal lung diseases. 1521 37

Human embryonic stemlike cells (hESCs) are pluripotent cells derived from blastocysts. Differentiating hESCs into respiratory lineages may benefit respiratory therapeutic programs. We previously demonstrated that 24% of all mouse embryonic stem cell (mESC) derivatives cocultured with embryonic day 11.5 (E11.5) mouse lung rudiments display immunoreactivity to the pneumonocyte II specific marker surfactant-associated protein C (Sftpc). Here we further investigate the effects of this inductive niche in terms of its competence to induce hESC derivative SFTPC immunoreactivity and the expression of other markers of terminal lung secretory units. When hESCs were cocultured as single cells, clumps of approximately 10 cells or embryoid bodies (EBs), hESC derivatives formed pan-keratin-positive epithelial tubules at high frequency (>30% of all hESC derivatives). However, human-specific SFTPC immunoreactivity associated with tubule formation only at low frequency (<0.1% of all hESC derivatives). Human-specific SFTPD and secretoglobin family 1A member 1 (SCGB1A1, also known as CC10) transcripts were detected by PCR after prolonged culture. Expression of other terminal lung secretory unit markers (TITF1, SFTPA, and SFTPB) was not detected at any time point analyzed. On the other hand, hESC derivatives cultured as plated EBs in media previously demonstrated to induce Sftpc expression in isolated mouse fetal tracheal epithelium expressed all terminal lung secretory unit markers examined. mESCs and hESCs thus display fundamental differences in their response to the E11.5 mouse lung inductive niche, and these data provide an important step in the delineation of signaling mechanisms capable of efficiently inducing hESC differentiation into terminal secretory units of the lung.
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PMID:A murine respiratory-inducing niche displays variable efficiency across human and mouse embryonic stem cell species. 1722 Mar 77

Heat shock proteins HSPA4L and HSPA4 are closely related members of the HSP110 family and act as cochaperones. We generated Hspa4l(-/-)Hspa4(-/-) mice to investigate a functional complementarity between HSPA4L and HSPA4 during embryonic development. Hspa4l(-/-)Hspa4(-/-) embryos exhibited marked pulmonary hypoplasia and neonatal death. Compared with lungs of wild-type, Hspa4l(-/-), and Hspa4(-/-) embryos, Hspa4l(-/-)Hspa4(-/-) lungs were characterized by diminished saccular spaces and increased mesenchymal septa. Mesenchymal hypercellularity was determined to be due to an increased cell proliferation index and decreased cell death. A significant increase in expression levels of prosurvival protein B cell leukemia/lymphoma 2 may be the cause for inhibition of apoptotic process in lungs of Hspa4(-/-)Hspa4l(-/-) embryos. Accumulation of glycogen and diminished expression of surfactant protein B, prosurfactant protein C, and aquaporin 5 in saccular epithelium suggested impaired maturation of type II and type I pneumocytes in the Hspa4l(-/-)Hspa4(-/-) lungs. Further experiments showed a significant accumulation of ubiquitinated proteins in the lungs of Hspa4l(-/-)Hspa4(-/-) embryos, indicating an impaired chaperone activity. Our study demonstrates that HSPA4L and HSPA4 collaborate in embryonic lung maturation, which is necessary for adaptation to air breathing at birth.
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PMID:Respiratory distress and early neonatal lethality in Hspa4l/Hspa4 double-mutant mice. 2398 May 76

The current study investigated the mechanisms involved in the process of biophysical inhibition of pulmonary surfactant by polymeric nanoparticles (NP). The minimal surface tension of diverse synthetic surfactants was monitored in the presence of bare and surface-decorated (i.e. poloxamer 407) sub-100 nm poly(lactide) NP. Moreover, the influence of NP on surfactant composition (i.e. surfactant protein (SP) content) was studied. Dose-elevations of SP advanced the biophysical activity of the tested surfactant preparation. Surfactant-associated protein C supplemented phospholipid mixtures (PLM-C) were shown to be more susceptible to biophysical inactivation by bare NP than phospholipid mixture supplemented with surfactant protein B (PLM-B) and PLM-B/C. Surfactant function was hindered owing to a drastic depletion of the SP content upon contact with bare NP. By contrast, surface-modified NP were capable of circumventing unwanted surfactant inhibition. Surfactant constitution influences the extent of biophysical inhibition by polymeric NP. Steric shielding of the NP surface minimizes unwanted NP-surfactant interactions, which represents an option for the development of surfactant-compatible nanomedicines.
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PMID:Biophysical inhibition of pulmonary surfactant function by polymeric nanoparticles: role of surfactant protein B and C. 2508 69