Defective Surfactant Secretion in a Mouse Model of Hermansky-Pudlak Syndrome

Guttentag, Susan H.; Akhtar, Amana; Tao, Jianmin; Atochina, Elena N.; Rusiniak, Michael E.; Swank, Richard T.; Bates, Sandra R.

doi:10.1165/rcmb.2004-0293oc

Cited by 71 publications

(66 citation statements)

References 50 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Figure 3B). This is in contrast to our prior report, in which we did not find differences in large and small aggregate total SP-D levels in comparing WT and EPPE animals at 16 weeks of age (7). In the present study we used an antibody with higher specificity for mouse (and human) SP-D (as described in the online supplement), and analyzed equal volumes of unfractionated BAL for total SP-D (4, 7).…”

Section: Resultscontrasting

confidence: 77%

“…In our prior study we normalized total SP-D immunoblotting data to BAL total protein and total phospholipid. This normalization presented a problem in retrospect because of elevated total protein and reduced total phospholipid in BAL from EPPE mice, as we and others have reported (4,7), leading us to conclude that total SP-D was not altered in the EPPE mice. In the present study we instead reported total SP-D in equivalent volumes of BAL from EPPE mice ( Figure 3) and patients with HPS1 ( Figure 5), and found dramatic differences that progressed with age in EPPE mice, and with disease severity in patients with HPS1.…”

Section: Discussionmentioning

confidence: 70%

See 1 more Smart Citation

Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

Atochina‐Vasserman

Bates

Zhang

et al. 2011

Am J Respir Crit Care Med

Self Cite

View full text Add to dashboard Cite

Rationale: The pulmonary phenotype of Hermansky-Pudlak syndrome (HPS) in adults includes foamy alveolar type 2 cells, inflammation, and lung remodeling, but there is no information about ontogeny or early disease mediators. Objectives: To establish the ontogeny of HPS lung disease in an animal model, examine disease mediators, and relate them to patients with HPS1. Methods: Mice with mutations in both HPS1/pale ear and HPS2/ AP3B1/pearl (EPPE mice) were studied longitudinally. Total lung homogenate, lung tissue sections, and bronchoalveolar lavage (BAL) were examined for phospholipid, collagen, histology, cell counts, chemokines, surfactant protein D (SP-D), and S-nitrosylated SP-D. Isolated alveolar epithelial cells were examined for expression of inflammatory mediators, and chemotaxis assays were used to assess their importance. Pulmonary function test results and BAL from patients with HPS1 and normal volunteers were examined for clinical correlation. Measurements and Main Results: EPPE mice develop increased total lung phospholipid, followed by a macrophage-predominant pulmonary inflammation, and lung remodeling including fibrosis.

show abstract

Section: Resultscontrasting

confidence: 77%

Section: Discussionmentioning

confidence: 70%

Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

Atochina‐Vasserman

Bates

Zhang

et al. 2011

Am J Respir Crit Care Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mouse models of the human disease Hermansky-Pudlak syndrome also demonstrate altered surfactant homeostasis. However, unlike Gpr116 Dexon17 , Sftpd 2/2 , and Csf2 2/2 mice, mice with mutations in HermanskyPudlak syndrome-associated genes exhibit decreased alveolar pools of surfactant phospholipids and increased tissue phospholipid levels due to defects in surfactant trafficking and decreased secretion in type II cells (42)(43)(44). Taken together, our data support the hypothesis that GPR116 controls alveolar surfactant pool sizes by negatively regulating surfactant secretion from type II cells.…”

Section: Surfactant In Gpr116supporting

confidence: 76%

Orphan G Protein–Coupled Receptor GPR116 Regulates Pulmonary Surfactant Pool Size

Bridges

Ludwig

Müeller

et al. 2013

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Pulmonary surfactant levels within the alveoli are tightly regulated to maintain lung volumes and promote efficient gas exchange across the air/blood barrier. Quantitative and qualitative abnormalities in surfactant are associated with severe lung diseases in children and adults. Although the cellular and molecular mechanisms that control surfactant metabolism have been studied intensively, the critical molecular pathways that sense and regulate endogenous surfactant levels within the alveolus have not been identified and constitute a fundamental knowledge gap in the field. In this study, we demonstrate that expression of an orphan G protein-coupled receptor, GPR116, in the murine lung is developmentally regulated, reaching maximal levels 1 day after birth, and is highly expressed on the apical surface of alveolar type I and type II epithelial cells. To define the physiological role of GPR116 in vivo, mice with a targeted mutation of the Gpr116 locus, Gpr116 Dexon17, were generated. Gpr116 Dexon17 mice developed a profound accumulation of alveolar surfactant phospholipids at 4 weeks of age (12-fold) that was further increased at 20 weeks of age (30-fold). Surfactant accumulation in Gpr116Dexon17 mice was associated with increased saturated phosphatidylcholine synthesis at 4 weeks and the presence of enlarged, lipid-laden macrophages, neutrophilia, and alveolar destruction at 20 weeks. mRNA microarray analyses indicated that P2RY2, a purinergic receptor known to mediate surfactant secretion, was induced in Gpr116Dexon17 type II cells. Collectively, these data support the concept that GPR116 functions as a molecular sensor of alveolar surfactant lipid pool sizes by regulating surfactant secretion.Keywords: pulmonary surfactant; G protein-coupled receptors; GPR116; surfactant metabolism; alveolar epithelium Pulmonary surfactant is synthesized by alveolar type II cells and is primarily composed of phospholipids, which constitute 80% of the total mass. The remaining components include neutral lipids, the lipid-associated surfactant proteins SFTPB and SFTPC, and the hydrophilic surfactant proteins SFTPA and SFTPD (1, 2). Saturated phosphatidylcholine (SatPC) is uniquely enriched in surfactant and, in concert with SFTPB and SFTPC, is fundamentally required to reduce surface tension at the air/liquid interface within the alveolus (3, 4). After synthesis, the lipid and lipidassociated proteins SFTPB and SFTPC are routed to and stored in membrane-enclosed secretory organelles called lamellar bodies. Through constitutive pathways or upon stimulation by secretagogues (including purines [5,6], b-agonists [7][8][9], and adenosine [10, 11]) or mechanical stretch (12), lamellar bodies fuse with the plasma membrane and are exocytosed from type II cells into the alveolar space.The quantity of surfactant in the mammalian lung, referred to as surfactant pool size, increases dramatically during late gestation to facilitate the transition to air breathing at birth. In the fetal lung, the majority of surfactant is stored within type I...

show abstract

“…It is thus likely that the BLOC-1-dependent pathway that we have defined is ubiquitous in mammals, but it has been exploited by specialized cell types for delivery of specific cargo to LROs, such as melanosomes, platelet dense granules, and lung lamellar bodies, and/or to synaptic vesicles (McGarry et al, 2002;Talbot et al, 2004;Bray et al, 2005;Guttentag et al, 2005). Our data suggest that at least one critical cargo protein is targeted from early endosomes to each of these organelles in a BLOC-1-dependent manner.…”

Section: Discussionmentioning

confidence: 75%

BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related Organelles

Setty

Tenza

Truschel

et al. 2007

MBoC

199

342

View full text Add to dashboard Cite

Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defects in the formation and function of lysosome-related organelles such as melanosomes. HPS in humans or mice is caused by mutations in any of 15 genes, five of which encode subunits of biogenesis of lysosome-related organelles complex (BLOC)-1, a protein complex with no known function.Here, we show that BLOC-1 functions in selective cargo exit from early endosomes toward melanosomes. BLOC-1-deficient melanocytes accumulate the melanosomal protein tyrosinase-related protein-1 (Tyrp1), but not other melanosomal proteins, in endosomal vacuoles and the cell surface due to failed biosynthetic transit from early endosomes to melanosomes and consequent increased endocytic flux. The defects are corrected by restoration of the missing BLOC-1 subunit. Melanocytes from HPS model mice lacking a different protein complex, BLOC-2, accumulate Tyrp1 in distinct downstream endosomal intermediates, suggesting that BLOC-1 and BLOC-2 act sequentially in the same pathway. By contrast, intracellular Tyrp1 is correctly targeted to melanosomes in melanocytes lacking another HPS-associated protein complex, adaptor protein (AP)-3. The results indicate that melanosome maturation requires at least two cargo transport pathways directly from early endosomes to melanosomes, one pathway mediated by AP-3 and one pathway mediated by BLOC-1 and BLOC-2, that are deficient in several forms of HPS. INTRODUCTIONHermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by hypopigmentation, prolonged bleeding, and sometimes ceroid accumulation, lung fibrosis, and/or immune defects leading to premature death Wei, 2006). HPS or a similar disorder in mice results from mutations in any of at least 15 genes (Wei, 2006). All of these genes are ubiquitously expressed, but their mutation in HPS affects mainly the generation and function of selected tissuespecific lysosome-related organelles (LROs;Bonifacino, 2004;Di Pietro and Dell'Angelica, 2005). Those LROs that are most severely affected in all forms of HPS-pigment cell melanosomes, platelet dense granules, and lung lamellar bodies-are unique in that they coexist with bona fide lysosomes in their respective cell types (Dell'Angelica et al., 2000;Marks and Seabra, 2001). The 15 known HPS-associated genes have been identified, and although the products of most are thought to participate in trafficking events that are uniquely required to form this class of LRO, the function of only a few is understood in detail.The genes disrupted in human HPS-7 (Li et al., 2003) and HPS-8 (Morgan et al., 2006) and in the mouse HPS models pallid, muted, reduced pigmentation (rp), cappuccino, and sandy encode five of the eight known subunits of a stable protein complex known as biogenesis of lysosome-related organelles complex (BLOC)-1 (Falcon-Perez et al., 2002;Moriyama and Bonifacino, 2002;Ciciotte et al., 2003;Li et al., 2003;Gwynn et al., 2004;Starcevic and Dell'Angelica, 2004). To date, no specific subcellular function has been assigned...

show abstract

Defective Surfactant Secretion in a Mouse Model of Hermansky-Pudlak Syndrome

Cited by 71 publications

References 50 publications

Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

Orphan G Protein–Coupled Receptor GPR116 Regulates Pulmonary Surfactant Pool Size

BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related Organelles

Contact Info

Product

Resources

About