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A Mutation in the Surfactant Protein C Gene Associated with Familial Interstitial Lung Disease

Lawrence Nogee et al.Feb 22, 2001

Interstitial lung diseases are a heterogeneous group of disorders that are poorly understood at a molecular level.1,2 The cause is often unknown, and the histologic diagnoses used in adults may represent different disease processes in children.3–5 For example, cases of desquamative interstitial pneumonitis reported in infants are often more severe and refractory to treatment than those reported in adults.6,7 Many of these cases probably represent chronic pneumonitis of infancy.8,9 The lungs in patients with chronic pneumonitis of infancy are characterized by interstitial thickening with mesenchymal cells, rather than by an inflammatory infiltrate, and an alveolar infiltrate . . .

Genetics

Internal Medicine

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ABCA3Gene Mutations in Newborns with Fatal Surfactant Deficiency

Sergey Shulenin et al.Mar 24, 2004

Pulmonary surfactant forms a lipid-rich monolayer that coats the airways of the lung and is essential for proper inflation and function of the lung. Surfactant is produced by alveolar type II cells, stored intracellularly in organelles known as lamellar bodies, and secreted by exocytosis. The gene for ATP-binding cassette transporter A3 (ABCA3) is expressed in alveolar type II cells, and the protein is localized to lamellar bodies, suggesting that it has an important role in surfactant metabolism.

Genetics

Biochemistry

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Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice.

Jean Clark et al.Aug 15, 1995

Surfactant protein B (SP-B) is an 8.7-kDa, hydrophobic protein that enhances the spreading and stability of surfactant phospholipids in the alveolus. To further assess the role of SP-B in lung function, the SP-B gene was disrupted by homologous recombination in murine mouse embryonic stem cells. Mice with a single mutated SP-B allele (+/-) were unaffected, whereas homozygous SP-B -/- offspring died of respiratory failure immediately after birth. Lungs of SP-B -/- mice developed normally but remained atelectatic in spite of postnatal respiratory efforts. SP-B protein and mRNA were undetectable and tubular myelin figures were lacking in SP-B -/- mice. Type II cells of SP-B -/- mice contained no fully formed lamellar bodies. While the abundance of SP-A and SP-C mRNAs was not altered, an aberrant form of pro-SP-C, 8.5 kDa, was detected, and fully processed SP-C peptide was markedly decreased in lung homogenates of SP-B -/- mice. Ablation of the SP-B gene disrupts the routing, storage, and function of surfactant phospholipids and proteins, causing respiratory failure at birth.

Biochemistry

Molecular Biology

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Early restriction of peripheral and proximal cell lineages during formation of the lung

Anne‐Karina Perl et al.Jul 26, 2002

To establish the timing of lineage restriction among endodermal derivatives, we developed a method to label permanently subsets of lung precursor cells at defined times during development by using Cre recombinase to activate floxed alkaline phosphatase or green fluorescent protein genes under control of doxycycline-dependent surfactant protein C promoter. Extensive or complete labeling of peripheral lung, thyroid, and thymic epithelia, but not trachea, bronchi, or gastrointestinal tract occurred when mice were exposed to doxycycline from embryonic day (E) 4.5 to E6.5. Nonoverlapping cell lineages of conducting airways (trachea and bronchi), as distinct from those of peripheral airways (bronchioles, acini, and alveoli), were established well before formation of the definitive lung buds at E9-9.5. At E11.5, the labeled precursors of peripheral lung were restricted to relatively few cells along the bronchial tubes and clusters in bronchial tips and lateral buds. Thereafter, these cells underwent marked expansion to form the entire gas-exchange region in the lung. This study demonstrates early restriction of endodermal progenitor cells forming peripheral as compared with proximal airways, identifies distinct cell lineages in conducting airways, and distinguishes neuroepithelial and tracheal-bronchial gland cell lineages from those lining peripheral regions of the lung. This system for conditional gene addition or deletion is useful for the study of lung morphogenesis and gene function in vivo, and identifies progenitor cells that may serve as useful targets for cell or gene replacement for pulmonary disorders.

Genetics

Molecular Biology

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Tissue-specific regulation of the alpha-myosin heavy chain gene promoter in transgenic mice.

Arun Subramaniam et al.Dec 1, 1991

The intergenic region between the mouse alpha-myosin heavy chain (MHC) and beta-MHC genes was analyzed in terms of its ability to drive gene expression in transgenic mice. Earlier, we reported that the entire intergenic region was sufficient to direct expression of the bacterial chloramphenicol acetyl transferase reporter gene in a tissue-specific and developmental stage-specific manner. Additional transgenic lines have been generated which include two deletions. The first deletion, alpha-3, which lacks the distal 2.5 kilobase pairs of the upstream region, is competent to direct tissue- and developmental-specific expression of the transgene. A larger deletion, in which only 138 base pairs upstream of the transcriptional start site remain, shows no chloramphenicol acetyltransferase activity in either muscle or non-muscle tissue. Tissue surveys of transgene expression indicated low levels of activity in the lung, and analyses via the polymerase chain reaction confirmed the presence of the endogenous alpha-MHC gene transcripts in this tissue. Subsequently, an alpha-MHC gene-specific riboprobe was used to detect the cognate transcripts in lung sections by in situ hybridization. The data show that, in the lung, the transcripts are localized to the thick intimal wall of the veins and venules.

Genetics

Molecular Biology

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Diffuse Lung Disease in Young Children

Gail Deutsch et al.Sep 21, 2007

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Internal Medicine

Surgery

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Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung.

Kevin Peters et al.Jul 1, 1994

Philosophy

Law

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Interleukin-1β Causes Pulmonary Inflammation, Emphysema, and Airway Remodeling in the Adult Murine Lung

Urpo Lappalainen et al.Jan 25, 2005

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Immunology

Physiology

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Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice

Susan Wert et al.May 9, 2000

Targeted ablation of the surfactant protein D (SP-D) gene caused chronic inflammation, emphysema, and fibrosis in the lungs of SP-D (−/−) mice. Although lung morphology was unperturbed during the first 2 weeks of life, airspace enlargement was observed by 3 weeks and progressed with advancing age. Inflammation consisted of hypertrophic alveolar macrophages and peribronchiolar-perivascular monocytic infiltrates. These abnormalities were associated with increased activity of the matrix metalloproteinases, MMP2 and MMP9, and immunostaining for MMP9 and MMP12 in alveolar macrophages. Hydrogen peroxide production by isolated alveolar macrophages also was increased significantly (10-fold). SP-D plays a critical role in the suppression of alveolar macrophage activation, which may contribute to the pathogenesis of chronic inflammation and emphysema.

Biochemistry

Immunology

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Altered surfactant function and structure in SP-A gene targeted mice.

Thomas Korfhagen et al.Sep 3, 1996

The surfactant protein A (SP-A) gene was disrupted by homologous recombination in embryonic stem cells that were used to generate homozygous SP-A-deficient mice. SP-A mRNA and protein were not detectable in the lungs of SP-A(-/-) mice, and perinatal survival of SP-A(-/-) mice was not altered compared with wild-type mice. Lung morphology, surfactant proteins B-D, lung tissue, alveolar phospholipid pool sizes and composition, and lung compliance in SP-A(-/-) mice were unaltered. At the highest concentration tested, surfactant from SP-A(-/-) mice produced the same surface tension as (+/+) mice. At lower concentrations, minimum surface tensions were higher for SP-A(-/-) mice. At the ultrastructural level, type II cell morphology was the same in SP-A(+/+) and (-/-) mice. While alveolar phospholipid pool sizes were unperturbed, tubular myelin figures were decreased in the lungs of SP-A(-/-) mice. A null mutation of the murine SP-A gene interferes with the formation of tubular myelin without detectably altering postnatal survival or pulmonary function.

Biochemistry

Molecular Biology

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Biochemistry

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