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Lawrence M Nogee - One of the best experts on this subject based on the ideXlab platform.

  • a novel SurfaCtant Protein C gene mutation assoCiated with progressive respiratory failure in infanCy
    Pediatric Pulmonology, 2017
    Co-Authors: Melissa Kaori Silva Litao, Lawrence M Nogee, Don Hayes, Saurabh Chiwane, Geoffrey Kurland, Lokesh Guglani
    Abstract:

    Mutations of the SurfaCtant Protein C (SPC) gene (SFTPC) have been assoCiated with Childhood interstitial lung disease (ChILD) with variable age of onset, severity of lung disease, and outComes. We report a novel mutation in SFTPC [C.435G->A, p.(Gln145)] that was assoCiated with onset of symptoms in early infanCy, progressive respiratory failure with need for prolonged meChaniCal ventilatory support, and eventual lung transplant at 1 year of age. While the mutation was not prediCted to alter the amino aCid sequenCe of the SP-C preCursor Protein, analysis of SP-C transCripts demonstrated skipping of exon 4. BeCause of limited data about the outComes of infants with SFTPC mutations, we ConduCted a systematiC review of all the SFTPC mutations reported in the literature in order to define their presenting features, CliniCal and radiologiC features, and outComes. Further advanCes in our understanding of ChILD and Creation of an international registry will help to traCk these patients and their outComes. Pediatr Pulmonol. 2017;52:57-68. © 2016 Wiley PeriodiCals, InC.

  • natural history of five Children with SurfaCtant Protein C mutations and interstitial lung disease
    Pediatric Pulmonology, 2014
    Co-Authors: Avraham Avital, Lawrence M Nogee, Avigdor Hevroni, Simon Godfrey, Shlomo Cohen, C Maayan, Samir Nusair, Chaim Springer
    Abstract:

    Interstitial lung diseases in infants and Children are unCommon and may be Caused by speCifiC inborn errors of SurfaCtant metabolism. Five Children with open lung biopsy diagnosed interstitial lung disease were followed (mean of 27.2 years) and evaluated for SurfaCtant Protein gene mutations. Four of the Children were originally diagnosed as desquamative interstitial pneumonitis and one as ChroniC interstitial pneumonitis. All had good response to Chloroquine or hydroxyChloroquine treatment for periods of 7-38 months. Lung funCtion tests, inCremental exerCise tests, and rentgenologiCal studies were performed in the Children. SurfaCtant Protein gene mutations were searChed in all the patients and in part of their families. Three of the patients, aged now 32, 29, and 37 years, feel well and have normal lung funCtion, while two of the patients, both females, aged 28 and 37 years, ConduCt normal aCtivities of daily living, have healthy Children but have CliniCal, physiologiCal and rentgenologiCal evidenCe of restriCtive lung disease. All five patients were found to have SurfaCtant Protein C gene (SFTPC) mutations, three of them with the most Common mutation (p.I73T) and the other two with new mutations of SurfaCtant Protein C gene (p.I38F and p.V39L). We ConClude that deteCtion of SurfaCtant Protein mutations should be attempted in all Children presenting with interstitial lung disease. Furthermore, treatment with hydroxyChloroquine should be Considered in Children with SFTPC mutations. ProspeCtive evaluation of hydroxyChloroquine therapy in a greater number of patients is needed.

  • neonatal respiratory failure due to a novel mutation in the SurfaCtant Protein C gene
    Journal of Perinatology, 2010
    Co-Authors: Brandon S Poterjoy, Y Vibert, Martha Solavisner, Jane E Mcgowan, Gary A Visner, Lawrence M Nogee
    Abstract:

    A full-term infant developed respiratory distress immediately after birth, requiring a prolonged Course of extra-Corporeal membrane oxygenation, followed by high-frequenCy ventilation. She was unable to wean off meChaniCal ventilation, required traCheostomy, and ultimately lung transplantation. A novel mutation in the SurfaCtant C Protein gene was identified as the Cause of her lung disease.

  • heterozygosity for abCa3 mutations modifies the severity of lung disease assoCiated with a SurfaCtant Protein C gene sftpC mutation
    Pediatric Research, 2007
    Co-Authors: Janine E Bullard, Lawrence M Nogee
    Abstract:

    Heterozygous SFTPC mutations have been assoCiated with adult and pediatriC interstitial lung disease (pILD). InheritanCe is autosomal dominant, but de novo mutations may Cause sporadiC disease. SFTPC mutations have been assoCiated with variable onset of symptoms, ranging from early infanCy to late adulthood. The underlying meChanisms for this variability are unknown. ReCently, mutations in ABCA3 (enCoding member A3 of the adenosine triphosphate-binding Cassette family of transporters) were identified as a Cause of pILD. To test the hypothesis that ABCA3 mutations modify the severity of lung disease in individuals with SFTPC mutations, we sequenCed ABCA3 from four symptomatiC infants with the same SFTPC mutation, a substitution of isoleuCine by threonine in Codon 73 (I73T). EaCh infant developed respiratory symptoms by 2 mo of age and inherited the mutation from an asymptomatiC parent. Three of the four infants were also heterozygous for an ABCA3 mutation, whiCh was inherited from the parent without SFTPC I73T. The finding of heterozygosity for ABCA3 mutations in severely affeCted infants with SFTPC I73T, and independent inheritanCe from disease-free parents supports that ABCA3 aCts as a modifier gene for the phenotype assoCiated with an SFTPC mutation.

  • a Common mutation in the SurfaCtant Protein C gene assoCiated with lung disease
    The Journal of Pediatrics, 2005
    Co-Authors: Scott H Cameron, Aaron Hamvas, Jeffrey A Whitsett, Susan E Wert, Marco Somaschini, Paola Carrera, Gail H Deutsch, Lawrence M Nogee
    Abstract:

    ObjeCtive To determine the Contribution of the SurfaCtant Protein C (SP-C) I73T mutation to lung disease. Study design GenomiC DNA was obtained from 116 Children with interstitial lung disease (ILD) or ChroniC lung disease of unClear Cause and from 166 Control subjeCts and was sCreened for the I73T mutation using an allele-speCifiC polymerase Chain reaCtion assay. Results The I73T mutation was found on 7 of 232 SP-C alleles from 7 unrelated Children with ILD but was not found on 332 Control SP-C alleles ( P ConClusions These findings support the hypothesis that the I73T mutation predisposes to or Causes lung disease.

Jeffrey A Whitsett - One of the best experts on this subject based on the ideXlab platform.

  • Compensatory roles of foxa1 and foxa2 during lung morphogenesis
    Journal of Biological Chemistry, 2005
    Co-Authors: Huajing Wan, Susan E Wert, Klaus H. Kaestner, Sharon Dingle, Valerie Besnard, Siewlan Ang, Mildred T Stahlman, Jeffrey A Whitsett
    Abstract:

    Foxa1 and Foxa2 are Closely related family members of the Foxa group of transCription faCtors that are Coexpressed in subsets of respiratory epithelial Cells throughout lung morphogenesis. Shared patterns of expression, Conservation of DNA binding, and transCriptional aCtivation domains indiCate that they may serve Complementary funCtions in the regulation of gene expression during lung morphogenesis. Whereas branChing morphogenesis of the fetal lung oCCurs normally in the Foxa2Delta/Delta and Foxa1-/- miCe, deletion of both Foxa1 and Foxa2 (in Foxa2Delta/Delta, Foxa1-/- miCe) inhibited Cell proliferation, epithelial Cell differentiation, and branChing. Dilation of terminal lung tubules and deCreased branChing were observed as early as embryoniC day 12.5. Foxa1 and Foxa2 regulated Shh (soniC hedgehog) and Shh-dependent genes in the respiratory epithelial Cells that influenCed the expression of genes in the pulmonary mesenChyme that are required for branChing morphogenesis. Epithelial Cell differentiation, as indiCated by laCk of expression of SurfaCtant Protein B, SurfaCtant Protein C, the Clara Cell seCretory Protein, and Foxj1, was inhibited. Foxa family members regulate signaling and transCriptional programs required for morphogenesis and Cell differentiation during formation of the lung.

  • a Common mutation in the SurfaCtant Protein C gene assoCiated with lung disease
    The Journal of Pediatrics, 2005
    Co-Authors: Scott H Cameron, Aaron Hamvas, Jeffrey A Whitsett, Susan E Wert, Marco Somaschini, Paola Carrera, Gail H Deutsch, Lawrence M Nogee
    Abstract:

    ObjeCtive To determine the Contribution of the SurfaCtant Protein C (SP-C) I73T mutation to lung disease. Study design GenomiC DNA was obtained from 116 Children with interstitial lung disease (ILD) or ChroniC lung disease of unClear Cause and from 166 Control subjeCts and was sCreened for the I73T mutation using an allele-speCifiC polymerase Chain reaCtion assay. Results The I73T mutation was found on 7 of 232 SP-C alleles from 7 unrelated Children with ILD but was not found on 332 Control SP-C alleles ( P ConClusions These findings support the hypothesis that the I73T mutation predisposes to or Causes lung disease.

  • taz interaCts with ttf 1 and regulates expression of SurfaCtant Protein C
    Journal of Biological Chemistry, 2004
    Co-Authors: Kwon Sik Park, Jeffrey A Whitsett, Tina Di Palma, Jeong Ho Hong, Michael B Yaffe, Mariastella Zannini
    Abstract:

    Thyroid transCription faCtor 1 (TTF-1/Nkx-2.1) plays a CritiCal role in lung morphogenesis and regulates the expression of lung-speCifiC genes, inCluding the SurfaCtant Proteins required for pulmonary funCtion after birth. The aCtivity of TTF-1 is influenCed by its interaCtions with other transCription faCtors and CoaCtivators, inCluding CBP/p300 and SRC-1. In this study, we have identified poly(ADP-ribose) polymerases (PARP-2 and PARP-1) as TTF-1 interaCting Proteins that influenCe its transCriptional aCtivity. Endogenous PARP-2 was CoimmunopreCipitated from transformed mouse lung epithelial Cell (MLE15) extraCts with TTF-1 and was identified by mass speCtrometry. PARP-1 and Ku70/Ku80 were also CoimmunopreCipitated from the Cell extraCts with TTF-1. The E domain of PARP-2 interaCted via the C-terminal domain of TTF-1. Both PARP-1 and PARP-2 enhanCed the aCtivity of the promoter of SurfaCtant Protein-B (Sftpb gene) but not other SurfaCtant Proteins in vitro. PARP-2 was seleCtively expressed in epithelial Cells of the ConduCting and peripheral lung tubules of the fetal mouse lung from embryoniC day 12.5 and was deteCted in bronChial epithelial Cells in the adult lung at Cellular sites Consistent with that of SurfaCtant Protein B. PARP-2 and PARP-1 interaCt with TTF-1 and regulate the expression of SurfaCtant Protein B, a Protein required for lung funCtion.

  • stat 3 is required for pulmonary homeostasis during hyperoxia
    Journal of Clinical Investigation, 2004
    Co-Authors: Isamu Hokuto, Susan E Wert, Machiko Ikegami, Mitsuhiro Yoshida, Kiyoshi Takeda, Shizuo Akira, Annekarina T Perl, William M Hull, Jeffrey A Whitsett
    Abstract:

    ACute lung injury syndromes remain Common Causes of morbidity and mortality in adults and Children. Cellular and physiologiC meChanisms maintaining pulmonary homeostasis during lung injury remain poorly understood. In the present study, the Stat-3 gene was seleCtively deleted in respiratory epithelial Cells by Conditional expression of Cre-reCombinase under Control of the SurfaCtant Protein C gene promoter. Cell-seleCtive deletion of Stat-3 in respiratory epithelial Cells did not alter prenatal lung morphogenesis or postnatal lung funCtion. However, exposure of adult Stat-3-deleted miCe to 95% oxygen Caused a more rapidly progressive lung injury assoCiated with alveolar Capillary leak and aCute respiratory distress. Epithelial Cell injury and inflammatory responses were inCreased in the Stat-3-deleted miCe. SurfaCtant Proteins and lipids were deCreased or absent in alveolar lavage material. IntratraCheal treatment with exogenous SurfaCtant Protein B improved survival and lung histology in Stat-3-deleted miCe during hyperoxia. Expression of Stat-3 in respiratory epithelial Cells is not required for lung formation, but plays a CritiCal role in maintenanCe of SurfaCtant homeostasis and lung funCtion during oxygen injury.

  • HydrophobiC SurfaCtant Proteins in lung funCtion and disease.
    The New England journal of medicine, 2002
    Co-Authors: Jeffrey A Whitsett, Timothy E. Weaver
    Abstract:

    Pulmonary SurfaCtants Consist of phospholipids and the hydrophobiC Proteins SurfaCtant Protein B and SurfaCtant Protein C. These SurfaCtants keep the alveoli in the lung open to the atmosphere. Mutations in the genes enCoding these Proteins Cause a variety of pulmonary syndromes. The pulmonary diseases assoCiated with some of these mutations exemplify the ConsequenCes of the aCCumulation of misfolded Proteins in tissue.

Timothy E. Weaver - One of the best experts on this subject based on the ideXlab platform.

  • 4 phenylbutyriC aCid treatment resCues traffiCking and proCessing of a mutant SurfaCtant Protein C
    American Journal of Respiratory Cell and Molecular Biology, 2012
    Co-Authors: Gareth Stewart, Ross Ridsdale, Emily P. Martin, Karunyakanth Mandapaka, Timothy E. Weaver
    Abstract:

    Mutations in the SFTPC gene, enCoding SurfaCtant Protein-C (SP-C), are assoCiated with interstitial lung disease (ILD). Knowledge of the intraCellular fate of mutant SP-C is essential in the design of therapies to CorreCt traffiCking/proCessing of the proProtein, and to prevent the formation of CytotoxiC aggregates. We assessed the potential of a ChemiCal Chaperone to CorreCt the traffiCking and proCessing of three disease-assoCiated mutant SP-C Proteins. HEK293 Cells were stably transfeCted with wild-type (SP-C(WT)) or mutant (SP-C(L188Q), SP-C(Δexon4), or SP-C(I73T)) SP-C, and Cell lines with a similar expression of SP-C mRNA were identified. The effeCts of the ChemiCal Chaperone 4-phenylbutyriC aCid (PBA) and lysosomotropiC drugs on intraCellular traffiCking to the endolysosomal pathway and the subsequent Conversion of SP-C proProtein to mature peptide were assessed. Despite Comparable SP-C mRNA expression, proProtein ConCentrations varied greatly: SP-C(I73T) was more abundant than SP-C(WT) and was loCalized to the Cell surfaCe, whereas SP-C(Δexon4) was barely deteCtable. In Contrast, SP-C(L188Q) and SP-C(WT) proProtein ConCentrations were Comparable, and a small amount of SP-C(L188Q) was loCalized to the endolysosomal pathway. PBA treatment restored the traffiCking and proCessing of SP-C(L188Q) to SP-C(WT) ConCentrations, but did not CorreCt the mistraffiCking of SP-C(I73T) or resCue SP-C(Δexon4). PBA treatment also promoted the aggregation of SP-C proProteins, inCluding SP-C(L188Q). This study provides proof of the prinCiple that a ChemiCal Chaperone Can CorreCt the mistraffiCking and proCessing of a disease-assoCiated mutant SP-C proProtein.

  • MeCkel-Gruber Syndrome Protein MKS3 Is Required for EndoplasmiC RetiCulum-assoCiated Degradation of SurfaCtant Protein C
    The Journal of biological chemistry, 2009
    Co-Authors: Mei Wang, James P Bridges, Timothy E. Weaver
    Abstract:

    Autosomal dominant mutations in the SFTPC gene are assoCiated with idiopathiC pulmonary fibrosis, a progressive lethal interstitial lung disease. Mutations that Cause misfolding of the enCoded proProtein SurfaCtant Protein C (SP-C) trigger endoplasmiC retiCulum (ER)-assoCiated degradation, a pathway that segregates terminally misfolded substrate for retrotransloCation to the Cytosol and degradation by proteasome. MiCroarray sCreens for genes involved in SP-C ER-assoCiated degradation identified MKS3/TMEM67, a loCus previously linked to the Ciliopathy MeCkel-Gruber syndrome. In this study, MKS3 was identified as a membrane glyCoProtein predominantly loCalized to the ER. Expression of MKS3 was up-regulated by genetiC or pharmaCologiCal induCers of ER stress. The ER lumenal domain of MKS3 interaCted with a Complex that inCluded mutant SP-C and assoCiated Chaperones, whereas the region prediCted to enCode the transmembrane domains of MKS3 interaCted with CytosoliC p97. Deletion of the transmembrane and CytosoliC domains abrogated interaCtion of MKS3 with p97 and resulted in aCCumulation of mutant SP-C proProtein; knoCkdown of MKS3 also inhibited degradation of mutant SP-C. These results support a model in whiCh MKS3 links the ER lumenal quality Control maChinery with the CytosoliC degradation apparatus.

  • erdj4 and erdj5 are required for endoplasmiC retiCulum assoCiated Protein degradation of misfolded SurfaCtant Protein C
    Molecular Biology of the Cell, 2008
    Co-Authors: Mei Dong, James P Bridges, Karen S Apsley, Timothy E. Weaver
    Abstract:

    Mutations in the SFTPC gene assoCiated with interstitial lung disease in human patients result in misfolding, endoplasmiC retiCulum (ER) retention, and degradation of the enCoded SurfaCtant Protein...

  • expression of a human SurfaCtant Protein C mutation assoCiated with interstitial lung disease disrupts lung development in transgeniC miCe
    Journal of Biological Chemistry, 2003
    Co-Authors: James P Bridges, Lawrence M Nogee, Susan E Wert, Timothy E. Weaver
    Abstract:

    SurfaCtant Protein C (SP-C) is a seCreted transmembrane Protein that is exClusively expressed by alveolar type II epithelial Cells of the lung. SP-C assoCiates with SurfaCtant lipids to reduCe surfaCe tension within the alveolus, maintaining lung volume at end expiration. Mutations in the gene enCoding SP-C (SFTPC) have reCently been linked to ChroniC lung disease in Children and adults. The goal of this study was to determine whether a disease-linked mutation in SFTPC Causes lung disease in transgeniC miCe. The SFTPC mutation, designated g.1728 G --> A, results in the deletion of exon4, generating a trunCated form of SP-C (SP-C(Deltaexon4)). CDNA enCoding SP-C(Deltaexon4) was Constitutively expressed in type II epithelial Cells of transgeniC miCe. Viable F0 transgene-positive miCe were not generated after two separate rounds of pronuClear injeCtions. HistologiCal analysis of lung tissue harvested from embryoniC day 17.5 F0 transgene-positive fetuses revealed that SP-C(Deltaexon4) Caused a dose-dependent disruption in branChing morphogenesis of the lung assoCiated with epithelial Cell CytotoxiCity. Transient expression of SP-C(Deltaexon4) in isolated type II epithelial Cells or HEK293 Cells resulted in inComplete proCessing of the mutant proProtein, a dose-dependent inCrease in BiP transCription, trapping of the proProtein in the endoplasmiC retiCulum, and rapid degradation via a proteasome-dependent pathway. Taken together, these data suggest that the g.1728 G --> A mutation Causes misfolding of the SP-C proProtein with subsequent induCtion of the unfolded Protein response and endoplasmiC retiCulum-assoCiated degradation pathways ultimately resulting in disrupted lung morphogenesis.

  • expression of a human SurfaCtant Protein C mutation assoCiated with interstitial lung disease disrupts lung development in transgeniC miCe
    Journal of Biological Chemistry, 2003
    Co-Authors: James P Bridges, Lawrence M Nogee, Susan E Wert, Timothy E. Weaver
    Abstract:

    SurfaCtant Protein C (SP-C) is a seCreted transmembrane Protein that is exClusively expressed by alveolar type II epithelial Cells of the lung. SP-C assoCiates with SurfaCtant lipids to reduCe surfaCe tension within the alveolus, maintaining lung volume at end expiration. Mutations in the gene enCoding SP-C (SFTPC) have reCently been linked to ChroniC lung disease in Children and adults. The goal of this study was to determine whether a disease-linked mutation in SFTPC Causes lung disease in transgeniC miCe. The SFTPC mutation, designated g.1728 G → A, results in the deletion of exon4, generating a trunCated form of SP-C (SP-CΔexon4). CDNA enCoding SP-CΔexon4 was Constitutively expressed in type II epithelial Cells of transgeniC miCe. Viable F0 transgene-positive miCe were not generated after two separate rounds of pronuClear injeCtions. HistologiCal analysis of lung tissue harvested from embryoniC day 17.5 F0 transgene-positive fetuses revealed that SP-CΔexon4 Caused a dose-dependent disruption in branChing morphogenesis of the lung assoCiated with epithelial Cell CytotoxiCity. Transient expression of SP-CΔexon4 in isolated type II epithelial Cells or HEK293 Cells resulted in inComplete proCessing of the mutant proProtein, a dose-dependent inCrease in BiP transCription, trapping of the proProtein in the endoplasmiC retiCulum, and rapid degradation via a proteasome-dependent pathway. Taken together, these data suggest that the g.1728 G → A mutation Causes misfolding of the SP-C proProtein with subsequent induCtion of the unfolded Protein response and endoplasmiC retiCulum-assoCiated degradation pathways ultimately resulting in disrupted lung morphogenesis.

Susan E Wert - One of the best experts on this subject based on the ideXlab platform.

  • Compensatory roles of foxa1 and foxa2 during lung morphogenesis
    Journal of Biological Chemistry, 2005
    Co-Authors: Huajing Wan, Susan E Wert, Klaus H. Kaestner, Sharon Dingle, Valerie Besnard, Siewlan Ang, Mildred T Stahlman, Jeffrey A Whitsett
    Abstract:

    Foxa1 and Foxa2 are Closely related family members of the Foxa group of transCription faCtors that are Coexpressed in subsets of respiratory epithelial Cells throughout lung morphogenesis. Shared patterns of expression, Conservation of DNA binding, and transCriptional aCtivation domains indiCate that they may serve Complementary funCtions in the regulation of gene expression during lung morphogenesis. Whereas branChing morphogenesis of the fetal lung oCCurs normally in the Foxa2Delta/Delta and Foxa1-/- miCe, deletion of both Foxa1 and Foxa2 (in Foxa2Delta/Delta, Foxa1-/- miCe) inhibited Cell proliferation, epithelial Cell differentiation, and branChing. Dilation of terminal lung tubules and deCreased branChing were observed as early as embryoniC day 12.5. Foxa1 and Foxa2 regulated Shh (soniC hedgehog) and Shh-dependent genes in the respiratory epithelial Cells that influenCed the expression of genes in the pulmonary mesenChyme that are required for branChing morphogenesis. Epithelial Cell differentiation, as indiCated by laCk of expression of SurfaCtant Protein B, SurfaCtant Protein C, the Clara Cell seCretory Protein, and Foxj1, was inhibited. Foxa family members regulate signaling and transCriptional programs required for morphogenesis and Cell differentiation during formation of the lung.

  • a Common mutation in the SurfaCtant Protein C gene assoCiated with lung disease
    The Journal of Pediatrics, 2005
    Co-Authors: Scott H Cameron, Aaron Hamvas, Jeffrey A Whitsett, Susan E Wert, Marco Somaschini, Paola Carrera, Gail H Deutsch, Lawrence M Nogee
    Abstract:

    ObjeCtive To determine the Contribution of the SurfaCtant Protein C (SP-C) I73T mutation to lung disease. Study design GenomiC DNA was obtained from 116 Children with interstitial lung disease (ILD) or ChroniC lung disease of unClear Cause and from 166 Control subjeCts and was sCreened for the I73T mutation using an allele-speCifiC polymerase Chain reaCtion assay. Results The I73T mutation was found on 7 of 232 SP-C alleles from 7 unrelated Children with ILD but was not found on 332 Control SP-C alleles ( P ConClusions These findings support the hypothesis that the I73T mutation predisposes to or Causes lung disease.

  • progressive lung disease and SurfaCtant dysfunCtion with a deletion in SurfaCtant Protein C gene
    American Journal of Respiratory Cell and Molecular Biology, 2004
    Co-Authors: Aaron Hamvas, Lawrence M Nogee, Susan E Wert, Brian P Hackett, Frances V White, Pamela Schuler, Charles B Huddleston, Eric N Mendeloff, Fong Fu Hsu, Linda W Gonzales
    Abstract:

    Mutations in the SurfaCtant Protein (SP)-C gene are responsible for familial and sporadiC interstitial lung disease (ILD). The ConsequenCes of suCh mutations on pulmonary SurfaCtant Composition and funCtion are poorly understood. To determine the effeCts of a mutation in the SP-C gene on SurfaCtant, we obtained lung tissue at the time of transplantation from a 14-mo-old infant with progressive ILD. An in-frame 9-bp deletion spanning Codons 91–93 in Exon 3 of the SP-C gene was present on one allele; neither parent Carried this deletion. SP-C mRNA was present in normal size and amount. By immunofluoresCenCe, proSP-C was aggregated within alveolar Type II Cells in a Compartment separate from SP-B. In airway SurfaCtant, there was little or no mature SP-B or SP-C; SP-A Content was inCreased. Minimum surfaCe tension was inCreased (20 mN/m, normal < 5 mN/m). Type II Cells Contained normal and disorganized appearing lamellar bodies by eleCtron miCrosCopy. This spontaneous deletion on one allele of the SP-C gene w...

  • stat 3 is required for pulmonary homeostasis during hyperoxia
    Journal of Clinical Investigation, 2004
    Co-Authors: Isamu Hokuto, Susan E Wert, Machiko Ikegami, Mitsuhiro Yoshida, Kiyoshi Takeda, Shizuo Akira, Annekarina T Perl, William M Hull, Jeffrey A Whitsett
    Abstract:

    ACute lung injury syndromes remain Common Causes of morbidity and mortality in adults and Children. Cellular and physiologiC meChanisms maintaining pulmonary homeostasis during lung injury remain poorly understood. In the present study, the Stat-3 gene was seleCtively deleted in respiratory epithelial Cells by Conditional expression of Cre-reCombinase under Control of the SurfaCtant Protein C gene promoter. Cell-seleCtive deletion of Stat-3 in respiratory epithelial Cells did not alter prenatal lung morphogenesis or postnatal lung funCtion. However, exposure of adult Stat-3-deleted miCe to 95% oxygen Caused a more rapidly progressive lung injury assoCiated with alveolar Capillary leak and aCute respiratory distress. Epithelial Cell injury and inflammatory responses were inCreased in the Stat-3-deleted miCe. SurfaCtant Proteins and lipids were deCreased or absent in alveolar lavage material. IntratraCheal treatment with exogenous SurfaCtant Protein B improved survival and lung histology in Stat-3-deleted miCe during hyperoxia. Expression of Stat-3 in respiratory epithelial Cells is not required for lung formation, but plays a CritiCal role in maintenanCe of SurfaCtant homeostasis and lung funCtion during oxygen injury.

  • expression of a human SurfaCtant Protein C mutation assoCiated with interstitial lung disease disrupts lung development in transgeniC miCe
    Journal of Biological Chemistry, 2003
    Co-Authors: James P Bridges, Lawrence M Nogee, Susan E Wert, Timothy E. Weaver
    Abstract:

    SurfaCtant Protein C (SP-C) is a seCreted transmembrane Protein that is exClusively expressed by alveolar type II epithelial Cells of the lung. SP-C assoCiates with SurfaCtant lipids to reduCe surfaCe tension within the alveolus, maintaining lung volume at end expiration. Mutations in the gene enCoding SP-C (SFTPC) have reCently been linked to ChroniC lung disease in Children and adults. The goal of this study was to determine whether a disease-linked mutation in SFTPC Causes lung disease in transgeniC miCe. The SFTPC mutation, designated g.1728 G --> A, results in the deletion of exon4, generating a trunCated form of SP-C (SP-C(Deltaexon4)). CDNA enCoding SP-C(Deltaexon4) was Constitutively expressed in type II epithelial Cells of transgeniC miCe. Viable F0 transgene-positive miCe were not generated after two separate rounds of pronuClear injeCtions. HistologiCal analysis of lung tissue harvested from embryoniC day 17.5 F0 transgene-positive fetuses revealed that SP-C(Deltaexon4) Caused a dose-dependent disruption in branChing morphogenesis of the lung assoCiated with epithelial Cell CytotoxiCity. Transient expression of SP-C(Deltaexon4) in isolated type II epithelial Cells or HEK293 Cells resulted in inComplete proCessing of the mutant proProtein, a dose-dependent inCrease in BiP transCription, trapping of the proProtein in the endoplasmiC retiCulum, and rapid degradation via a proteasome-dependent pathway. Taken together, these data suggest that the g.1728 G --> A mutation Causes misfolding of the SP-C proProtein with subsequent induCtion of the unfolded Protein response and endoplasmiC retiCulum-assoCiated degradation pathways ultimately resulting in disrupted lung morphogenesis.

Michael F. Beers - One of the best experts on this subject based on the ideXlab platform.

  • epithelial expression of an interstitial lung disease assoCiated mutation in SurfaCtant Protein C modulates reCruitment and aCtivation of key myeloid Cell populations in miCe
    Journal of Immunology, 2019
    Co-Authors: Alessandro Venosa, Scott J Russo, Surafel Mulugeta, Jeremy Katzen, Yaniv Tomer, Meghan Kopp, Sarita Jamil, Michael F. Beers
    Abstract:

    Patients with idiopathiC pulmonary fibrosis (IPF) often experienCe preCipitous deteriorations, termed "aCute exaCerbations" (AE), marked by diffuse alveolitis and altered gas exChange, resulting in a signifiCant loss of lung funCtion or mortality. The missense isoleuCine to threonine substitution at position 73 (I73T) in the alveolar type 2 Cell-restriCted SurfaCtant Protein-C (SP-C) gene (SFTPC) has been linked to CliniCal IPF. To better understand the sequenCe of events that impaCt AE-IPF, we leveraged a murine model of induCible SP-CI73T (SP-CI73T/I73TFlp+/- ) expression. Following administration of tamoxifen to 8-12-wk-old miCe, an upregulation of SftpCI73T initiated a diffuse lung injury marked by inCreases in bronChoalveolar lavage fluid (BALF) Protein and histoChemiCal evidenCe of CD45+ and CD11b+ Cell infiltrates. Flow Cytometry of Collagenase-digested lung Cells revealed a transient, early reduCtion in SigleCFhiCD11blowCD64hiCD11Chi maCrophages, Countered by the sequential aCCumulation of SigleCFloCD11b+CD64-CD11C-CCR2+Ly6C+ immature maCrophages (3 d), Ly6G+ neutrophils (7 d), and SigleCFhiCD11bhiCD11Clo eosinophils (2 wk). By mRNA analysis, BALF Cells demonstrated a time-dependent phenotypiC shift from a proinflammatory (3 d) to an anti-inflammatory/profibrotiC aCtivation state, along with serial elaboration of monoCyte and eosinophil reCruitment faCtors. The i.v. administration of Clodronate effeCtively reduCed total BALF Cell numbers, CCR2+ immature maCrophages, and eosinophil influx while improving survival. In Contrast, resident maCrophage depletion from the intratraCheal delivery of Clodronate liposomes enhanCed SftpCI73T -induCed mortality. These results using SftpCI73T miCe provide a detailed ontogeny for AE-IPF driven by alveolar epithelial dysfunCtion that induCes a polyCellular inflammation initiated by the early influx of proinflammatory CCR2+Ly6Chi immature maCrophages.

  • a non briChos sftpC mutant sp Ci73t linked to interstitial lung disease promotes a late bloCk in maCroautophagy disrupting Cellular proteostasis and mitophagy
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2015
    Co-Authors: Arie Hawkins, Susan H Guttentag, Surafel Mulugeta, Robin R Deterding, William K Funkhouser, Jennifer L Goralski, Shampa Chatterjee, Michael F. Beers
    Abstract:

    Mutation of threonine for isoleuCine at Codon 73 (I73T) in the human SurfaCtant Protein C (hSP-C) gene (SFTPC) aCCounts for a signifiCant portion of SFTPC mutations assoCiated with interstitial lun...

  • a nonaggregating SurfaCtant Protein C mutant is misdireCted to early endosomes and disrupts phospholipid reCyCling
    Traffic, 2011
    Co-Authors: Michael F. Beers, Arie Hawkins, Jean Ann Maguire, Adam Kotorashvili, Ming Zhao, Jennifer L Newitt, Wenge Ding, Scott J Russo, Susan H Guttentag, Linda W Gonzales
    Abstract:

    Interstitial lung disease in both Children and adults has been linked to mutations in the lung-speCifiC SurfaCtant Protein C (SFTPC) gene. Among these, the missense mutation [isoleuCine to threonine at Codon 73 = human SurfaCtant Protein C (hSP-C(I73T) )] aCCounts for ∼30% of all desCribed SFTPC mutations. We reported previously that unlike the BRICHOS misfolding SFTPC mutants, expression of hSP-C(I73T) induCes lung remodeling and alveolar lipoProteinosis without a substantial EndoplasmiC RetiCulum (ER) stress response or ER-mediated intrinsiC apoptosis. We show here that, in Contrast to its wild-type Counterpart that is direCtly routed to lysosomal-like organelles for proCessing, SP-C(I73T) is misdireCted to the plasma membrane and subsequently internalized to the endoCytiC pathway via early endosomes, leading to the aCCumulation of abnormally proCessed proSP-C isoforms. FunCtionally, Cells expressing hSP-C(I73T) demonstrated both impaired uptake and degradation of SurfaCtant phospholipid, thus providing a moleCular meChanism for the observed lipid aCCumulation in patients expressing hSP-C(I73T) through the disruption of normal phospholipid reCyCling. Our data provide evidenCe for a novel Cellular meChanism for Conformational Protein-assoCiated diseases and suggest a paradigm for mistargeted Proteins involved in the disruption of the endosomal/lysosomal sorting maChinery.

  • misfolded briChos sp C mutant Proteins induCe apoptosis via Caspase 4 and CytoChrome C related meChanisms
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2007
    Co-Authors: Surafel Mulugeta, Jean Ann Maguire, Adam Kotorashvili, Jennifer L Newitt, Scott J Russo, Michael F. Beers
    Abstract:

    Several mutations within the BRICHOS domain of SurfaCtant Protein C (SP-C) have been linked to interstitial lung disease. ReCent studies have suggested that these mutations Cause misfolding of the ...

  • a SurfaCtant Protein C preCursor Protein briChos domain mutation Causes endoplasmiC retiCulum stress proteasome dysfunCtion and Caspase 3 aCtivation
    American Journal of Respiratory Cell and Molecular Biology, 2005
    Co-Authors: Surafel Mulugeta, Scott J Russo, Vu Nguyen, Madesh Muniswamy, Michael F. Beers
    Abstract:

    BRICHOS is a domain found in several Proteins Consisting of ∼ 100 amino aCids with sequenCe and struCtural similarities. Mutations in BRICHOS domain have been assoCiated with both degenerative and proliferative diseases in several nonpulmonary organs, although the pathogeniC meChanisms are largely undefined. ReCently, several mutations in SurfaCtant Protein C (SP-C) mapping to the BRICHOS domain loCated within the proProtein (proSP-C) have been linked to interstitial lung diseases. In vitro expression of one of these BRICHOS mutants, the exon 4 deletion (hSP-CΔexon4), promotes a dominant-negative perinuClear aggregation of the Protein. The present study CharaCterizes the traffiCking behavior and pathogeniC ConsequenCes resulting from hSP-CΔexon4 expression. Time-lapse and Co-loCalization miCrosCopy studies demonstrated enhanCed green fluoresCent Protein (EGFP)/hSP-CΔexon4 expression in Calnexin-positive (endoplasmiC retiCulum [ER]) Compartment with subsequent time- and ConCentration-dependent development ...