SP-C-deficient (SP-C −/−) mice developed a severe pulmonary disorder associated with emphysema, monocytic infiltrates, epithelial cell dysplasia, and atypical accumulations of intracellular lipids in type II cells alveolar macrophages. Whereas tissue surfactant phospholipid pools were increased, levels other proteins not altered (SP-B) or modestly increased (SP-A SP-D). Analysis pressure-volume curves forced oscillatory dynamics demonstrated abnormal respiratory mechanics typical emphysema....

Durable reconstitution of the distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising therapy for diseases that result from alveolar damage. Here, we differentiate murine PSCs into self-renewing epithelial progenitors able to engraft injured immunocompetent, syngeneic mouse recipients. After transplantation, these mature in lung, assuming molecular phenotypes type 2 (AT2) and 1 (AT1) cells. months vivo, donor-derived cells retain their...

The purpose of this study was to identify culture conditions for maintenance isolated mouse type II cells with intact surfactant protein (SP) and phospholipid production. Type were from 6-wk-old mice cultured on Matrigel matrix-rat tail collagen (70:30 vol/vol) in bronchial epithelial cell growth medium minus hydrocortisone plus 5% charcoal-stripped FBS 10 ng/ml keratinocyte factor. Under these conditions, actively produced phospholipids proteins at least 7 days. Synthesis secretion SP-A,...

Surfactant protein B (SP-B) is an essential constituent of pulmonary surfactant. SP-B synthesized in alveolar type II cells as a preproprotein and processed to the mature peptide by cleavage NH2- COOH-terminal peptides. An aspartyl protease has been suggested cleave NH2-terminal propeptide resulting 25-kDa intermediate. Napsin, expressed cells, was detected fetal lung homogenates early day 16 gestation, 1 before onset expression processing. Napsin localized multivesicular bodies, site...

Mutations in the gene encoding SP-C (surfactant protein C; SFTPC) have been linked to interstitial lung disease (ILD) children and adults. Expression of index mutation, SP-CΔexon4, transiently transfected cells type II transgenic mice resulted misfolding proprotein, activation endoplasmic reticulum (ER) stress pathways, cytotoxicity. In this study, we show that stably adapted chronic ER imposed by constitutive expression SP-CΔexon4 via an NF-κB–dependent pathway. However, infection...

Endoplasmic reticulum–localized DnaJ 4 (ERdj4) is an immunoglobulin-binding protein (BiP) cochaperone and component of the endoplasmic reticulum–associated degradation (ERAD) pathway that functions to remove unfolded/misfolded substrates from ER lumen under conditions stress. To elucidate function ERdj4 in vivo, we disrupted locus using gene trap (GT) mutagenesis, leading hypomorphic expression mice homozygous for trapped allele (ERdj4 GT/GT ). Approximately half died perinatally associated...

Adaptation to respiration at birth depends upon the synthesis of pulmonary surfactant, a lipid-protein complex that reduces surface tension air-liquid interface in alveoli and prevents lung collapse during ventilatory cycle. Herein, we demonstrated gene encoding subunit endoplasmic reticulum membrane complex, EMC3, also known as TMEM111 (Emc3/Tmem111), was required for murine surfactant function birth. Conditional deletion Emc3 embryonic epithelial cells disrupted packaging lipids proteins,...

Rationale: The regeneration and replacement of lung cells or tissues from induced pluripotent stem cell- embryonic cell-derived represent future therapies for life-threatening pulmonary disorders but are limited by technical challenges to produce highly differentiated able maintain function. Functional tissue-containing airways, alveoli, vasculature, stroma have never been produced via directed differentiation (ESCs) cells. We sought all tissue components the bronchi alveoli embryo...

Surfactant protein D (SP-D) is a member of the collectin family innate host defense proteins. In lung, SP-D expressed primarily by type II cells. Gene-targeted SP-D-deficient [SP-D(-/-)] mice have three- to fivefold higher surfactant lipid pool sizes. However, synthesis and secretion cells catabolism alveolar macrophages are normal in SP-D(-/-) mice. Therefore, we hypothesized that might regulate homeostasis influencing structure, thereby altering its uptake Large (LA) small aggregate (SA)...

Pulmonary surfactant is a complex mixture of lipids and proteins that essential for postnatal function. Surfactant synthesized in alveolar type II cells stored as multi-bilayer membranes specialized secretory lysosome-related organelle (LRO), known the lamellar body (LB), prior to secretion into airspaces. Few LB have been identified mechanisms regulating formation trafficking this are poorly understood. Lamellar bodies were isolated from rat lungs, separated limiting membrane core...

Abstract Mitochondria synthesize select phospholipids but lack the machinery for synthesis of most abundant mitochondrial phospholipid, phosphatidylcholine (PC). Although phospholipid transfer protein Stard7 promotes uptake PC by mitochondria, importance this pathway and cellular homeostasis represents a significant knowledge gap. Haploinsufficiency is associated with exacerbation allergic airway disease in mice, including an increase epithelial barrier permeability. To test hypothesis that...

Lysozyme is one of the most abundant antimicrobial proteins in airspaces lung. Mice express two lysozyme genes, M and P, but only enzyme detected abundance lung tissues. Disruption locus significantly increased bacterial burden mortality following intratracheal infection with a Gram-negative bacterium. Unexpectedly, significant activity (muramidase activity) was uninfected M−/− mice, amounting to 25% wild-type mice. Muramidase mice associated P mRNA protein tissue bronchoalveolar lavage...

Ventilation throughout life is dependent on the formation of pulmonary alveoli, which create an extensive surface area in close apposition respiratory epithelium and endothelial cells microvascular enables efficient gas exchange. Morphogenesis alveoli initiates at late gestation humans early postnatal period mouse. Alveolar septation directed by complex signaling interactions among multiple cell types. Here, we demonstrate that IGF1 receptor gene (Igf1r) expression a subset fibroblasts...

Proteolytic processing of surfactant protein C (SP-C) proprotein in multivesicular bodies alveolar type II cells results a 35-residue mature peptide, consisting transmembrane domain and 10-residue extramembrane domain. SP-C peptide is stored lamellar (a lysosomal-like organelle) secreted with phospholipids into the space. This study was designed to identify required for sorting secretion this integral membrane peptide. Deletion analyses transiently transfected PC12 isolated mouse suggested...

Surfactant protein B (SP-B) mRNA and are restricted to alveolar Type II Clara cells in the respiratory epithelium. In order investigate function of SP-B these distinct cell types, transgenic mice were generated which expression was selectively restored or −/− mice. The 4.8-kilobase murine SP-C promoter used generate 3 lines expressed human (mSP-C/hSP-B). Likewise, 2.3-kilobase CCSP two (mCCSP/hSP-B). mSP-C/hSP-B mCCSP/hSP-B subsequently bred +/− express Selective restoration completely...

Surfactant protein B (SP-B) is detected in the airways as a sulfhydryl-dependent dimer (M(r) approximately 16,000). To test hypothesis that formation of homodimers critical for SP-B function, cysteine residue reported to be involved dimerization was mutated serine (Cys(248) --> Ser) and targeted distal respiratory epithelium transgenic mice. Transgenic lines which demonstrated appropriate processing, sorting, secretion human monomer were crossed with +/- mice achieve expression absence...

Section:ChooseTop of pageAbstract <<Materials and MethodsResultsDiscussionReferencesCITING ARTICLES

Section:ChooseTop of pageAbstract <<MATERIALS AND METHODSRESULTSDISCUSSIONReferencesCITING ARTICLES

Section:ChooseTop of pageAbstract <<Materials and MethodsResultsDiscussionReferencesCITING ARTICLES

Surfactant protein B (SP-B) is required for function of newborn and adult lung, partial deficiency has been associated with susceptibility to lung injury. In the present study, transgenic mice were produced in which expression SP-B type II epithelial cells was conditionally regulated. Concentrations maintained at 60-70% that normally control. Immunostaining demonstrated cellular heterogeneity protein. subsets staining decreased, immunostaining pro-SP-C increased lamellar body ultrastructure...

Section:ChooseTop of pageAbstract <<Materials and MethodsResultsDiscussionReferencesCITING ARTICLES

Mutations in the gene SFTPC, encoding surfactant protein C (SP-C), are associated with interstitial lung disease children and adults. To assess natural history of disease, we knocked a familial, disease-associated SFTPC mutation, L188Q (L184Q [LQ] mice), into mouse Sftpc locus. Translation mutant proprotein, proSP-CLQ, exceeded that proSP-CWT neonatal alveolar type 2 epithelial cells (AT2 cells) was transient activation oxidative stress apoptosis, leading to impaired expansion AT2 during...

The 79-amino acid, mature SP-B peptide contains three intramolecular disulfide bonds shared by all saposin-like proteins. This study tested the hypothesis that bond formed between cysteine residues 35 and 46 (residues 235 246 of proprotein) is essential for proper function SP-B. To test role this bridge in vivo, a construct was generated which human proprotein were mutated to serine cloned under control 3.7-kilobase hSP-C promoter (hSP-BC235S/C246S). In two transgenic mouse lines, expression...

Abstract KIF3A, the gene encoding kinesin family member 3A, is a susceptibility locus associated with asthma; however, mechanisms by which KIF3A might influence pathogenesis of disorder are unknown. In this study, we deleted mouse Kif3a in airway epithelial cells. Both homozygous and heterozygous gene–deleted mice were highly susceptible to aeroallergens from Aspergillus fumigatus house dust mite, resulting an asthma-like pathology characterized increased goblet cell metaplasia,...