Biomedical subjects

X He

Publications and source records attributed to X He.

At least 37 records · Page 2Linked to original sources

PubMed2001

A role for accessibility to self-peptide-self-MHC complexes in intrathymic negative selection.

Whether intrathymic-positive and -negative selection of conventional alpha beta T cells occur in anatomically distinct sites is a matter of debate. By using a system composed of two distinct immune receptors, the Y-Ae mAb and the 1H3.1 (V alpha 1/V beta 6) TCR, both directed against the 52--68 fragment of the I-E alpha-chain (E alpha 52--68) bound to I-A(b), we examined the occurrence of negative selection imposed in vivo by a self-peptide-self-MHC class II complex with differential tissue expression. 1H3.1 TCR-transgenic (Tg) mice were bred to mice having an I-E alpha transgene with expression directed to all MHC class II-positive cells, restricted to thymic epithelial cells, or restricted to B cells, dendritic cells, and medullary thymic epithelial cells. All 1H3.1 TCR/I-E alpha double-Tg mice revealed a severely diminished thymic cellularity. Their lymph node cells were depleted of V beta 6(+)CD4(+) cells and were unresponsive to E alpha 52--68 in vitro. The absolute number of CD4(+)CD8(+) thymocytes was drastically reduced in all combinations, indicating that negative selection caused by an endogenously expressed self-determinant can effectively occur in the thymic cortex in vivo. Moreover, both cortical epithelial cells and, interestingly, the few cortical dendritic cells were able to support negative selection of CD4(+)CD8(+) thymocytes, albeit with a distinct efficiency. Collectively, these observations support a model where, in addition to the avidity of the thymocyte/stromal cell interaction, in vivo negative selection of autoreactive TCR-Tg T cells is determined by accessibility to self-peptide-self-MHC complexes regardless of the anatomical site.

Animals↗

PubMed2001

Structure of an extracellular gp130 cytokine receptor signaling complex.

The activation of gp130, a shared signal-transducing receptor for a family of cytokines, is initiated by recognition of ligand followed by oligomerization into a higher order signaling complex. Kaposi's sarcoma-associated herpesvirus encodes a functional homolog of human interleukin-6 (IL-6) that activates human gp130. In the 2.4 angstrom crystal structure of the extracellular signaling assembly between viral IL-6 and human gp130, two complexes are cross-linked into a tetramer through direct interactions between the immunoglobulin domain of gp130 and site III of viral IL-6, which is necessary for receptor activation. Unlike human IL-6 (which uses many hydrophilic residues), the viral cytokine largely uses hydrophobic amino acids to contact gp130, which enhances the complementarity of the viral IL-6-gp130 binding interfaces. The cross-reactivity of gp130 is apparently due to a chemical plasticity evident in the amphipathic gp130 cytokine-binding sites.

Antigens, CD↗

PubMed2001

GABA(A) receptors containing (alpha)5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry.

GABA receptors within the mesolimbic circuitry have been proposed to play a role in regulating alcohol-seeking behaviors in the alcohol-preferring (P) rat. However, the precise GABA(A) receptor subunit(s) mediating the reinforcing properties of EtOH remains unknown. We examined the capacity of intrahippocampal infusions of an alpha5 subunit-selective ( approximately 75-fold) benzodiazepine (BDZ) inverse agonist [i.e., RY 023 (RY) (tert-butyl 8-(trimethylsilyl) acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate)] to alter lever pressing maintained by concurrent presentation of EtOH (10% v/v) and a saccharin solution (0.05% w/v). Bilateral (1.5-20 microgram) and unilateral (0.01-40 microgram) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 microgram). The competitive BDZ antagonist ZK 93426 (ZK) (7 microgram) reversed the RY-induced suppression on EtOH-maintained responding, confirming that the effect was mediated via the BDZ site on the GABA(A) receptor complex. Intrahippocampal modulation of the EtOH-maintained responding was site-specific; no antagonism by RY after intra-accumbens [nucleus accumbens (NACC)] and intraventral tegmental [ventral tegmental area (VTA)] infusions was observed. Because the VTA and NACC contain very high densities of alpha1 and alpha2 subunits, respectively, we determined whether RY exhibited a "negative" or "neutral" pharmacological profile at recombinant alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors expressed in Xenopus oocytes. RY produced "classic" inverse agonism at all alpha receptor subtypes; thus, a neutral efficacy was not sufficient to explain the failure of RY to alter EtOH responding in the NACC or VTA. The results provide the first demonstration that the alpha5-containing GABA(A) receptors in the hippocampus play an important role in regulating EtOH-seeking behaviors.

Animals↗

PubMed2001

Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III.

Mycolic acids (alpha-alkyl-beta-hydroxy long chain fatty acids) cover the surface of mycobacteria, and inhibition of their biosynthesis is an established mechanism of action for several key front-line anti-tuberculosis drugs. In mycobacteria, long chain acyl-CoA products (C(14)-C(26)) generated by a type I fatty-acid synthase can be used directly for the alpha-branch of mycolic acid or can be extended by a type II fatty-acid synthase to make the meromycolic acid (C(50)-C(56)))-derived component. An unusual Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein (ACP) synthase III (mtFabH) has been identified, purified, and shown to catalyze a Claisen-type condensation between long chain acyl-CoA substrates such as myristoyl-CoA (C(14)) and malonyl-ACP. This enzyme, presumed to play a key role in initiating meromycolic acid biosynthesis, was crystallized, and its structure was determined at 2.1-A resolution. The mtFabH homodimer is closely similar in topology and active-site structure to Escherichia coli FabH (ecFabH), with a CoA/malonyl-ACP-binding channel leading from the enzyme surface to the buried active-site cysteine residue. Unlike ecFabH, mtFabH contains a second hydrophobic channel leading from the active site. In the ecFabH structure, this channel is blocked by a phenylalanine residue, which constrains specificity to acetyl-CoA, whereas in mtFabH, this residue is a threonine, which permits binding of longer acyl chains. This same channel in mtFabH is capped by an alpha-helix formed adjacent to a 4-amino acid sequence insertion, which limits bound acyl chain length to 16 carbons. These observations offer a molecular basis for understanding the unusual substrate specificity of mtFabH and its probable role in regulating the biosynthesis of the two different length acyl chains required for generation of mycolic acids. This mtFabH presents a new target for structure-based design of novel antimycobacterial agents.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗

PubMed2001

An initial ATP-independent step in the unwinding of a herpes simplex virus type I origin of replication by a complex of the viral origin-binding protein and single-strand DNA-binding protein.

Using a spectrophotometric assay that measures the hyperchromicity that accompanies the unwinding of a DNA duplex, we have identified an ATP-independent step in the unwinding of a herpes simplex virus type 1 (HSV-1) origin of replication, Ori(s), by a complex of the HSV-1 origin binding protein (UL9 protein) and the HSV-1 single-strand DNA binding protein (ICP8). The sequence unwound is the 18-bp A + T-rich segment that links the two high-affinity UL9 protein binding sites, boxes I and II of Ori(s). P1 nuclease sensitivity of Ori(s) and single-strand DNA-dependent ATPase measurements of the UL9 protein indicate that, at 37 degrees C, the A + T-rich segment is sufficiently single stranded to permit the binding of ICP8. Binding of the UL9 protein to boxes I and II then results in the formation of the UL9 protein-ICP8 complex, that can, in the absence of ATP, promote unwinding of the A + T-rich segment. On addition of ATP, the helicase activity of the UL9 protein-ICP8 complex can unwind boxes I and II, permitting access of the replication machinery to the Ori(s) sequences.

Adenine↗

PubMed2001

Monte Carlo simulation of morphologies of self-assembled amphiphilic diblock copolymers in solution.

The Monte Carlo method has been applied to simulate the process of the self-assembling of amphiphilic diblock copolymers in a selective solvent. The simulations illustrated that the aggregates morphologies of A-b-B diblock copolymers in solution strongly depend on the length of corona-forming segments, i.e., with the decrease of the corona-forming segments, the transition of spherical micelles to rodlike aggregates occurs, which are in accord with the experimental results of Eisenberg and co-workers [Science 268, 1728 (1995); Macromolecules 32, 2239 (1999); 31, 3509 (1998); 29, 6359 (1996); 31, 9399 (1998)].

Journal Article↗

PubMed2001

Effector function of resting T cells: activation of synovial fibroblasts.

Synovial tissue in rheumatoid arthritis is characterized by infiltration with large numbers of T lymphocytes and APCs as well as hyperplasia of synovial fibroblasts. Current understanding of the pathogenesis of RA includes the concept that synovial fibroblasts, which are essential to cartilage and bone destruction, are regulated by cytokines derived primarily from monocyte-macrophage cells. Recently it has been found that synovial fibroblasts can also function as accessory cells for T cell activation by superantigens and other stimuli. We have now found that highly purified resting T cells, even in the absence of T cell mitogens, induce activation of synovial fibroblasts when cocultured for 6-24 h. Such activation was evident by induction or augmentation of mRNA for stromelysin, IL-6, and IL-8, gene products important in joint inflammation and joint destruction. Furthermore, increased production of IL-6 and IL-8 was quantitated by intracellular cytokine staining and flow cytometry. This technique, previously used for analysis of T cell function, was readily adaptable for assays of synovial fibroblasts. Resting T cells also induced synovial fibroblasts to produce PGE(2), indicating activation of expression of the cyclooxygenase 2 gene. Synergy was observed between the effects of IL-17, a cytokine derived from stimulated T cells that activates fibroblasts, and resting T lymphocytes. Various subsets of T cells, CD4(+), CD8(+), CD45RO(+), and CD45RA(+) all had comparable ability to induce synovial fibroblast activation. These results establish an Ag-independent effector function for resting T cells that is likely to be important in inflammatory compartments in which large numbers of T lymphocytes and fibroblasts can come into direct contact with each other.

Adjuvants, Immunologic↗

PubMed2001

Active site heterogeneity in dimethyl sulfoxide reductase from Rhodobacter capsulatus revealed by Raman spectroscopy.

Raman spectroscopy has been used to investigate the structure of the molybdenum cofactor in DMSO reductase from Rhodobacter capsulatus. Three oxidized forms of the enzyme, designated 'redox cycled', 'as prepared', and DMSOR(mod)D, have been studied using 752 nm laser excitation. In addition, two reduced forms of DMSO reductase, prepared either anaerobically using DMS or using dithionite, have been characterized. The 'redox cycled' form has a single band in the Mo=O stretching region at 865 cm(-1) consistent with other studies. This oxo ligand is found to be exchangeable directly with DMS(18)O or by redox cycling. Furthermore, deuteration experiments demonstrate that the oxo ligand in the oxidized enzyme has some hydroxo character, which is ascribed to a hydrogen bonding interaction with Trp 116. There is also evidence from the labeling studies for a modified dithiolene sulfur atom, which could be present as a sulfoxide. In addition to the 865 cm(-1) band, an extra band at 818 cm(-1) is observed in the Mo=O stretching region of the 'as prepared' enzyme which is not present in the 'redox cycled' enzyme. Based on the spectra of unlabeled and labeled DMS reduced enzyme, the band at 818 cm(-1) is assigned to the S=O stretch of a coordinated DMSO molecule. The DMSOR(mod)D form, identified by its characteristic Raman spectrum, is also present in the 'as prepared' enzyme preparation but not after redox cycling. The complex mixture of forms identified in the 'as prepared' enzyme reveals a substantial degree of active site heterogeneity in DMSO reductase.

Bacterial Proteins↗

PubMed2001

Conformational color polymorphism and control of crystallization of 5-methyl-2-[(4-methyl-2-nitrophenyl)amino]-3-thiophenecarbonitrile.

5-Methyl-2-[(4-methyl-2-nitrophenyl)amino]-3-thiophenecarbonitrile is an example of conformational and color polymorphism. The compound crystallizes in red (R), dark red (DR), light red (LR), and orange (O) modifications. There are two specific goals for this study. One is to characterize the complex thermodynamic relationship among these four known forms, and the other is to use the knowledge of the thermodynamic relationship to control the crystallization of these forms. The different forms were characterized by X-ray powder diffractometry as well as Fourier-transform infrared (FT-IR) and Raman spectroscopy; their complex thermodynamic relationships were determined by thermal analysis, solubility measurements, and slurry conversion studies. According to the solubility results, all forms are enantiotropically related: R is the thermodynamically most stable form above 60 degrees C, O is the most stable form between room temperature and 60 degrees C, LR is the most stable form below -15 degrees C, and DR is metastable throughout the entire temperature range. DR, LR, and O have very similar free energy at ambient temperature, which is the reason for the complex transition behavior. Finally, a schematic energy-temperature diagram was constructed that combines all experimental data in a comprehensive thermodynamic picture and provides insights into how to control the crystallization of the individual forms.

Calorimetry, Differential Scanning↗

PubMed2001

Survey of the distribution of red tide toxins (okadaic acid and dinophytoxin-1) in the Dalian Bay sea area of China by micellar electrokinetic capillary chromatography.

Two kinds of diarrhoetic shellfish toxins, okadaic acid (OA) and dinophytoxin-1 (DTX-1) were determined by micellar electrokinetic capillary chromatography (MEKC) with ultraviolet detection. A detection limit of 3.25 microg/mL for both of them was achieved. The UV absorbance of these toxins measured at 200 nm showed good linearity in the range of 6.25-200 microg/mL with R = 0.992 for OA and 0.997 for DTX-1. Three kinds of shellfish (Chlamys farreri, Mytilus edulis and Ruditaps philippinarum) collected from eight locations (sampling in the intertidal zone) along the Dalian Bay sea area of China were surveyed in February and May of 2000. Results indicated that three kinds of shellfish were contaminated by OA and DTX-1. Based on per gram of hepatopancreas in February, the contamination contents ranged from 0 to 1.26 microg for OA and from 0 to 1.82 microg for DTX-1, and in May, the contents ranged from 0 to 1.45 microg for OA and 0 to 2.56 microg for DTX-1. Among the eight locations, Hei Shi Jiao and Long Wang Tang were the most contaminated areas. Of the three kinds of shellfish, Mytilus edulis was the most significant species in accumulating OA and DTX-1.

Animals↗

PubMed2001

Enzyme replacement therapy in feline mucopolysaccharidosis I.

Enzyme replacement therapy (ERT) has long been considered an approach to treating lysosomal storage disorders caused by deficiency of lysosomal enzymes. ERT is currently used to treat Gaucher disease and is being developed for several lysosomal storage disorders now that recombinant sources of the enzymes have become available. We have continued development of ERT for mucopolysaccharidosis I (MPS I) using the feline model. Recombinant alpha-L-iduronidase was administered intravenously at low dose (approximately 0.1 mg/kg or 25,000 units/kg) to four cats and high dose (0.5 mg/kg or 125,000 units/kg) to two cats on a weekly basis for 3- or 6-month terms. Clinical examinations showed distinct clearing of corneal clouding in one cat although clinical effects in the others were not evident. Biochemical studies of the cats showed that the enzyme was distributed to a variety of tissues although the liver and spleen contained the highest enzyme activities. Glycosaminoglycan storage was decreased in liver and spleen, and the histologic appearance improved in liver, spleen, and renal cortex. Enzyme was not consistently detected in cerebral cortex, brainstem, or cerebellum and the histologic appearance and ganglioside profiles did not improve. A variety of other tissues showed low variable uptake of enzyme and no distinct improvement. IgG antibodies to alpha-L-iduronidase were observed in five cats with higher titers noted when higher doses were administered. Mild complement activation occurred in three cats. Enzyme replacement therapy was effective in reversing storage in some tissues at the biochemical and histologic level in MPS I cats but an improved tissue distribution and prevention of a significant immune response could make the therapy more effective.

Animals↗

PubMed2001

Attentional selection in the processing of hierarchical patterns: an ERP study.

The current study aimed to investigate the effect of attentional selection of distinctive local elements on the processing of hierarchically organized patterns. Event-related brain potentials (ERPs) were recorded from subjects during identifications of global or local shapes of hierarchical patterns where either all local elements were identical (homogeneous stimulus) or a local element closest to fixation was distinguished by color from others (pop-out stimulus). One group of subjects was presented with the homogeneous stimuli and required to identify global or local shapes in separate blocks of trials. The other group was presented with the pop-out stimuli and asked to attend to the unique local item in the local task. A global precedence effect was observed in behavioral data. ERPs showed enlarged posterior P1 and N2 amplitudes in the local relative to global conditions. Top-down attention to the pop-out item resulted in increased frontal/central N2 amplitudes in the local condition but eliminated the temporal/occipital N2 enhancement in the local relative to global conditions. Top-down attention to the pop-out item also increased local-to-global interference in reaction times and frontal N2 latencies. The results suggest that a frontal mechanism is involved in directing top-down attention to a specific local item whereas a temporal/occipital mechanism is engaged in an attentional filtering process in the identification of local shapes in hierarchical analysis.

Adult↗

PubMed2001

Differential sensitivity to inverse agonists of GABA(A)/benzodiazepine receptors in rats with genetic absence-epilepsy.

A strain of Wistar rats, genetic absence epilepsy rats from Strasbourg (GAERS), was selected and inbred over 40 generations for occurrence of spontaneous spike-wave discharges characteristic of absence seizures, simultaneously with a strain of non-epileptic rats (NER). GAERS demonstrate an excessive sensitivity to antagonists of the GABA(A) receptor. The sensitivity to convulsions induced by various inverse agonists of the GABA(A)/benzodiazepine receptor was compared in GAERS and NERs. The beta-carbolines FG 7142 and DMCM, and the imidazobenzodiazepines RO 19-4603 and the alpha 5-selective RY 024 were several times more convulsant in GAERS than in NERs. The largest differences were found with the non-selective RO 19-4603- and FG 7142. The proconvulsant imidazobenzodiazepine RO 15-4513, binding also to diazepam-insensitive receptors, had low efficacy. The high affinity binding of GABA(A)/BZD receptors with (3H) RO 15-1788 in the brain of naive rats and after administration of FG 7142 did not differ in GAERS and NERs. The data indicate that the hypersensitivity of GAERS to various inverse agonists of the GABA(A)/benzodiazepine receptor involves cortical GABA(A) receptors and is not related to differential activity of a subunit-selective receptor.

Animals↗

PubMed2001

Promiscuous antigen presentation by the nonclassical MHC Ib Qa-2 is enabled by a shallow, hydrophobic groove and self-stabilized peptide conformation.

BACKGROUND: Qa-2 is a nonclassical MHC Ib antigen, which has been implicated in both innate and adaptive immune responses, as well as embryonic development. Qa-2 has an unusual peptide binding specificity in that it requires two dominant C-terminal anchor residues and is capable of associating with a substantially more diverse array of peptide sequences than other nonclassical MHC. RESULTS: We have determined the crystal structure, to 2.3 A, of the Q9 gene of murine Qa-2 complexed with a self-peptide derived from the L19 ribosomal protein, which is abundant in the pool of peptides eluted from the Q9 groove. The 9 amino acid peptide is bound high in a shallow, hydrophobic binding groove of Q9, which is missing a C pocket. The peptide makes few specific contacts and exhibits extremely poor shape complementarity to the MHC groove, which facilitates the presentation of a degenerate array of sequences. The L19 peptide is in a centrally bulged conformation that is stabilized by intramolecular interactions from the invariant P7 histidine anchor residue and by a hydrophobic core of preferred secondary anchor residues that have minimal interaction with the MHC. CONCLUSIONS: Unexpectedly, the preferred secondary peptide residues that exhibit tenuous contact with Q9 contribute significantly to the overall stability of the peptide-MHC complex. The structure of this complex implies a "conformational" selection by Q9 for peptide residues that optimally stabilize the large bulge rather than making intimate contact with the MHC pockets.

Animals↗

PubMed2001

PARM: a practical utility for drug design.

To accommodate situations in which the 3D structure of the target receptor is not available, we have developed the Pseudo Atomic Receptor Model (PARM) software package. In this article we describe PARM and illustrate its use with three examples: elemenes (potential anticancer drugs), angiotensin converting enzyme inhibitors, and human HIV-1 inhibitors TTD (1,1,3-trioxo-2H, 4H-thieno[3,4-e][1,2,4] thiadiazine derivatives). The results show that PARM can build models with favorable cross-validation statistics (Rcv2 values 0.7-0.9) and give helpful SAR insight. PARM has certain advantages: (a) it can be used for many systems, regardless of whether the 3D structure of the receptor is known; (b) PARM models were demonstrated to be highly statistically reliable; and (c) PARM analyses are robust and reproducible.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2001

PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation.

Signaling mechanisms underlying neurotrophic regulation of synaptic transmission are not fully understood. Here we show that neurotrophin-3 (NT3)-induced potentiation of synaptic transmission at the neuromuscular synapses is blocked by inhibition of phosphoinositide-3 kinase, phospholipase C-gamma or the downstream IP3 receptors of phospholipase C-gamma, but not by inhibition of MAP kinase. However, neither stimulation of Ca2+ release from intracellular stores by photolysis of caged IP3, nor expression of a constitutively active phosphoinositide-3 kinase (PI3K*) in presynaptic motoneurons alone is sufficient to enhance transmission. Photo-uncaging of IP3 in neurons expressing PI3K* elicits a marked synaptic potentiation, mimicking the NT3 effect. These results reveal an involvement of PI3 kinase in transmitter release, and suggest that concomitant activation of PI3 kinase and IP3 receptors is both necessary and sufficient to mediate the NT3-induced synaptic potentiation.

Animals↗

PubMed2001

Growth factors regulate the survival and fate of cells derived from human neurospheres.

Cells isolated from the embryonic, neonatal, and adult rodent central nervous system divide in response to epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF-2), while retaining the ability to differentiate into neurons and glia. These cultures can be grown in aggregates termed neurospheres, which contain a heterogeneous mix of both multipotent stem cells and more restricted progenitor populations. Neurospheres can also be generated from the embryonic human brain and in some cases have been expanded for extended periods of time in culture. However, the mechanisms controlling the number of neurons generated from human neurospheres are poorly understood. Here we show that maintaining cell-cell contact during the differentiation stage, in combination with growth factor administration, can increase the number of neurons generated under serum-free conditions from 8% to > 60%. Neurotrophic factors 3 and 4 (NT3, NT4) and platelet-derived growth factor (PDGF) were the most potent, and acted by increasing neuronal survival rather than inducing neuronal phenotype. Following differentiation, the neurons could survive dissociation and either replating or transplantation into the adult rat brain. This experimental system provides a practically limitless supply of enriched, non-genetically transformed neurons. These should be useful for both neuroactive drug screening in vitro and possibly cell therapy for neurodegenerative diseases.

Animals↗

PubMed2001

Analysis of the lung pathology and alveolar macrophage function in the acid sphingomyelinase--deficient mouse model of Niemann-Pick disease.

Types A and B Niemann-Pick disease (NPD) are lipid storage diseases caused by the deficient activity of the lysosomal enzyme, acid sphingomyelinase (ASM). Type B NPD is associated with progressive pulmonary function decline and frequent respiratory infections. ASM knock-out (ASMKO) mice are available as a model for NPD, but the lung pathology in these mice has not been adequately characterized. This study shows that by 10 weeks of age ASMKO mice have a significantly higher number of cells in their pulmonary airspaces than normal mice, consisting primarily of enlarged and often multinucleated macrophages. These mice also have much higher levels of sphingomyelin in their airspaces at 10 weeks of age, and both cell numbers and sphingomyelin concentrations remain elevated until 26 weeks of age. In these older mice an increased number of neutrophils is also seen. The alveolar cell population in the ASMKO mice produces less superoxide when stimulated, but this can be corrected by providing recombinant ASM to the culture media. Elevated levels of the chemokines macrophage inflammatory protein-2 and macrophage inflammatory protein-1alpha were also present in the bronchoalveolar lavage fluid of ASMKO mice, and this correlated with increased production of these chemokines by cultured macrophages and enhanced immunostaining in situ. Also, lung histology showed increased cellularity in the alveolar walls of ASMKO mice, but no evidence of fibrosis. Ultrastructural analysis of the lungs showed that the ASMKO mice have similar pathologic features to human NPD patients, with variable lipid storage evident in type I pneumocytes, endothelial cells, and airway ciliated epithelia. The alveolar macrophage, however, was the most dramatically affected cell type in both mice and humans. These studies indicate that the ASMKO mice can be used as a model to study the lung pathology associated with NPD, and demonstrate that the cellular and biochemical analysis of pulmonary airspaces may be a useful approach to monitoring disease progression and/or treatment.

Animals↗