Biomedical subjects

H Denny Liggitt

Publications and source records attributed to H Denny Liggitt.

17 recordsLinked to original sources

PubMed2006

Redundant Toll-like receptor signaling in the pulmonary host response to Pseudomonas aeruginosa.

Activation of pulmonary defenses against Pseudomonas aeruginosa requires myeloid differentiation factor 88 (MyD88), an adaptor for Toll-like receptor (TLR) signaling. To determine which TLRs mediate recognition of P. aeruginosa, we measured cytokine responses of bone marrow cells from wild-type mice and mice lacking TLR2 (TLR2(-/-)), TLR4 (TLR4(-/-)), TLR2 and TLR4 (TLR2/4(-/-)), or MyD88 (MyD88(-/-)) to wild-type P. aeruginosa and to fliC P. aeruginosa, which lacks the TLR5 ligand flagellin. Mice also were challenged with aerosolized bacteria to determine cytokine responses, lung inflammation, and bacterial clearance. TNF induction required MyD88 and was absent in TLR2/4(-/-) cells in response to fliC but not wild-type P. aeruginosa, whereas TLR2(-/-) cells exhibited augmented responses. In vivo, TLR4(-/-) mice responded to wild-type P. aeruginosa with reduced cytokine production and inflammation, but intact bacterial clearance, while TLR2(-/-) mice had partially impaired cytokine responses and delayed bacterial killing despite normal inflammation. When challenged with fliC, MyD88(-/-) mice failed to mount early cytokine and inflammatory responses or control bacterial replication, resulting in necrotizing lung injury and lethal disseminated infection. TLR4(-/-) and TLR2/4(-/-) mice responded to fliC infection with severely limited inflammatory and cytokine responses but intact bacterial clearance. TLR2(-/-) mice had partially reduced cytokine responses but augmented inflammation and preserved bacterial killing. These data indicate that TLR4- and flagellin-induced signals mediate most of the acute inflammatory response to Pseudomonas and that TLR2 has a counterregulatory role. However, MyD88-dependent pathways, in addition to those downstream of TLR2, TLR4, and TLR5, are required for pulmonary defense against P. aeruginosa.

Animals↗

PubMed2006

Growth factor receptors as regulators of hematopoiesis.

Nearly 15 years have elapsed since the US Food and Drug Administration last approved a major new hematopoietic cytokine. Promiscuous binding to multiple receptors, or to receptors expressed by multiple tissues, reduces growth factor specificity and promotes side effects. Here we show that hematopoiesis can be differentially regulated using receptors rather than ligands. Conditional derivatives of both fibroblast growth factor receptor-1 (F36VFGFR1) and the thrombopoietin receptor (F36VMpl) induced a sustained expansion of mouse marrow cells ex vivo, and erythroid cells in vivo. Only F36VFGFR1 could support the ex vivo expansion of short-term repopulating hematopoietic stem cells (HSCs), the ex vivo survival of long-term repopulating HSCs, and the prolonged in vivo expansion of granulocytes, monocytes, and platelets. Only F36VMpl induced a response sufficiently rapid to accelerate recovery from radiation-induced anemia. These results establish receptors as a new class of hematopoietic regulators possessing activities unobtainable with growth factors.

Amino Acid Substitution↗

PubMed2006

New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 1): Identification of the nephrotoxic metabolic pathway.

BACKGROUND: Methoxyflurane nephrotoxicity results from biotransformation; inorganic fluoride is a toxic metabolite. Concern exists about potential renal toxicity from volatile anesthetic defluorination, but many anesthetics increase fluoride concentrations without consequence. Methoxyflurane is metabolized by both dechlorination to methoxydifluoroacetic acid (MDFA, which may degrade to fluoride) and O-demethylation to fluoride and dichloroacetatic acid. The metabolic pathway responsible for methoxyflurane nephrotoxicity has not, however, been identified, which was the aim of this investigation. METHODS: Experiments evaluated methoxyflurane metabolite formation and effects of enzyme induction or inhibition on methoxyflurane metabolism and toxicity. Rats pretreated with phenobarbital, barium sulfate, or nothing were anesthetized with methoxyflurane, and renal function and urine methoxyflurane metabolite excretion were assessed. Phenobarbital effects on MDFA metabolism and toxicity in vivo were also assessed. Metabolism of methoxyflurane and MDFA in microsomes from livers of pretreated rats was determined in vitro. RESULTS: Phenobarbital pretreatment increased methoxyflurane nephrotoxicity in vivo (increased diuresis and blood urea nitrogen and decreased urine osmolality) and induced in vitro hepatic microsomal methoxyflurane metabolism to inorganic fluoride (2-fold), dichloroacetatic acid (1.5-fold), and MDFA (5-fold). In contrast, phenobarbital had no influence on MDFA renal effects in vivo or MDFA metabolism in vitro or in vivo. MDFA was neither metabolized to fluoride nor nephrotoxic. Barium sulfate diminished methoxyflurane metabolism and nephrotoxicity in vivo. CONCLUSIONS: Fluoride from methoxyflurane anesthesia derives from O-demethylation. Phenobarbital increases in methoxyflurane toxicity do not seem attributable to methoxyflurane dechlorination, MDFA toxicity, or MDFA metabolism to another toxic metabolite, suggesting that nephrotoxicity is attributable to methoxyflurane O-demethylation. Fluoride, one of many metabolites from O-demethylation, may be toxic and/or reflect formation of a different toxic metabolite. These results may have implications for interpreting anesthetic defluorination, volatile anesthetic use, and methods to evaluate anesthetic toxicity.

Anesthetics, Inhalation↗

PubMed2006

New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 2): Identification of nephrotoxic metabolites.

BACKGROUND: Methoxyflurane nephrotoxicity results from its metabolism, which occurs by both dechlorination (to methoxydifluoroacetic acid [MDFA]) and O-demethylation (to fluoride and dichloroacetic acid [DCAA]). Inorganic fluoride can be toxic, but it remains unknown why other anesthetics, commensurately increasing systemic fluoride concentrations, are not toxic. Fluoride is one of many methoxyflurane metabolites and may itself cause toxicity and/or reflect formation of other toxic metabolite(s). This investigation evaluated the disposition and renal effects of known methoxyflurane metabolites. METHODS: Rats were given by intraperitoneal injection the methoxyflurane metabolites MDFA, DCAA, or sodium fluoride (0.22, 0.45, 0.9, or 1.8 mmol/kg followed by 0.11, 0.22, 0.45, or 0.9 mmol/kg on the next 3 days) at doses relevant to metabolite exposure after methoxyflurane anesthesia, or DCAA and fluoride in combination. Renal histology and function (blood urea nitrogen, urine volume, urine osmolality) and metabolite excretion in urine were assessed. RESULTS: Methoxyflurane metabolite excretion in urine after injection approximated that after methoxyflurane anesthesia, confirming the appropriateness of metabolite doses. Neither MDFA nor DCAA alone had any effects on renal function parameters or necrosis. Fluoride at low doses (0.22, then 0.11 mmol/kg) decreased osmolality, whereas higher doses (0.45, then 0.22 mmol/kg) also caused diuresis but not significant necrosis. Fluoride and DCAA together caused significantly greater tubular cell necrosis than fluoride alone. CONCLUSIONS: Methoxyflurane nephrotoxicity seems to result from O-demethylation, which forms both fluoride and DCAA. Because their co-formation is unique to methoxyflurane compared with other volatile anesthetics and they are more toxic than fluoride alone, this suggests a new hypothesis of methoxyflurane nephrotoxicity. This may explain why increased fluoride formation from methoxyflurane, but not other anesthetics, is associated with toxicity. These results may have implications for the interpretation of clinical anesthetic defluorination, use of volatile anesthetics, and the laboratory methods used to evaluate potential anesthetic toxicity.

Anesthesiology↗

PubMed2006

West Nile and St. Louis encephalitis virus antibody seroconversion, prevalence, and persistence in naturally infected pig-tailed macaques (Macaca nemestrina).

Pig-tailed macaques (Macaca nemestrina) naturally infected with West Nile virus were monitored from 1999 to 2005 to determine virus-specific antibody seroconversion, prevalence, and persistence. Antibodies persisted for up to 36 months, as detected by epitope-blocking enzyme-linked immunosorbent and hemagglutination inhibition assays. Exposure to cocirculating St. Louis encephalitis virus was evaluated by Western blotting and immunofluorescence assays.

Animals↗

PubMed2006

Comparison of commercially available and novel West Nile virus immunoassays for detection of seroconversion in pig-tailed macaques (Macaca nemestrina).

We report the assessment and validation of an NS1 epitope-blocking enzyme-linked immunosorbent assay (ELISA) for detection of antibodies to West Nile virus (WNV) in macaques. Sera from naturally infected Macaca nemestrina were tested by ELISA and plaque reduction neutralization test (PRNT). Results were correlated with hemagglutination inhibition (HAI) data. Our results demonstrate that the blocking ELISA rapidly and specifically detects WNV infection in M. nemestrina. In addition, the diagnostic value of 7 commercially available immunoassays (PanBio immunoglobulin [Ig] M ELISA, PanBio IgG ELISA, PanBio immunofluorescence assay (IFA), InBios IgG ELISA, InBios IgM ELISA, Focus Diagnostics IgG ELISA, and Focus Diagnostics IgM ELISA) in M. nemestrina was evaluated and compared with that of the epitope-blocking ELISA. The PanBio IgG ELISA was found to effectively diagnose WNV exposure in M. nemestrina. Further, PanBio IFA slides are fast and reliable screening tools for diagnosing flaviviral exposure in M. nemestrina.

Animals↗

PubMed2006

Detection of systemic amyloidosis in the pig-tailed macaque (Macaca nemestrina).

Secondary amyloidosis is a progressive systemic disease for which there is no reliable diagnostic assay, preventive measure, or treatment. In an attempt to elucidate an antemortem diagnosis, 30 female pig-tailed macaques (Macaca nemestrina) at the Washington National Primate Research Center were surveyed for amyloidosis. Amyloid was demonstrated histologically in 47% (14 of 30) of the animals. The distribution and severity of amyloid deposition was variable. Affected animals had a mean age (+/-1 standard deviation) of 13.2 +/- 4.9 y, which was significantly greater than the mean age of unaffected animals (9.3 +/- 4.1) y. Twelve tests were evaluated for detection of amyloidosis; the diagnostic value of each was determined through comparison of histologically positive and histologically negative animals. Diagnostic tests evaluated were endoscopic examination and biopsy of the stomach and colon, abdominal ultrasonography, hepatic radiology, serum amyloid A (SAA), endothelin 1, alpha-fetal protein, aspartate aminotransferase (AST), alanine aminotransferase, gamma-glutamyltransferase (GGT), alkaline phosphatase, cholesterol, blood urea nitrogen, total bilirubin, C-reactive proteins, and erythrocyte sedimentation rate. Amyloidotic animals demonstrated a distinctive serologic profile: elevated SAA, GGT, and AST in combination with decreased total protein and albumin. Radiology demonstrated hepatomegaly in animals with hepatic amyloid deposition. In the absence of known infection or trauma, an amyloidotic serologic profile and radiologic hepatomegaly are consistent with systemic amyloidosis in M. nemestrina.

Age Factors↗

PubMed2005

Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice.

The cytokine thymic stromal lymphopoietin (TSLP) has been linked to human allergic inflammatory diseases. We show here that TSLP expression was increased in the lungs of mice with antigen-induced asthma, whereas TSLP receptor-deficient mice had considerably attenuated disease. Lung-specific expression of a Tslp transgene induced airway inflammation and hyperreactivity characterized by T helper type 2 cytokines and increased immunoglobulin E. The lungs of Tslp-transgenic mice showed massive infiltration of leukocytes, goblet cell hyperplasia and subepithelial fibrosis. TSLP was capable of activating bone marrow-derived dendritic cells to upregulate costimulatory molecules and produce the T helper type 2 cell-attracting chemokine CCL17. These findings suggest that TSLP is an important factor necessary and sufficient for the initiation of allergic airway inflammation.

Allergens↗

PubMed2005

An essential role for non-bone marrow-derived cells in control of Pseudomonas aeruginosa pneumonia.

MyD88 is an adapter protein required for the induction of proinflammatory cytokines by most Toll-like receptors (TLR), and Pseudomonas aeruginosa expresses ligands for multiple TLRs. MyD88(-/-) (KO) mice are highly susceptible to aerosolized P. aeruginosa, failing to elicit an early inflammatory response and permitting a 3-log increase in bacterial CFU in the lungs by 24 h after infection. We hypothesized that alveolar macrophages are the first cells to recognize and kill aerosolized P. aeruginosa in an MyD88-dependent fashion due to their location within the airways. To determine which cells in the lungs mediate MyD88-dependent defenses against P. aeruginosa, we generated radiation bone marrow (BM) chimeras between MyD88KO and wild-type (WT) mice. MyD88KO mice transplanted with MyD88KO BM (MyD88KO-->MyD88KO mice) displayed uncontrolled bacterial replication, whereas all other chimeras controlled the infection by 24 h. However, at 4 h, both MyD88KO-->MyD88KO and WT-->MyD88KO mice permitted intrapulmonary bacterial replication, whereas MyD88KO-->WT and WT-->WT mice did not, indicating that the source of BM had little impact on the early control of infection. Similarly, the genotype of the recipient rather than that of the BM donor determined early neutrophil recruitment to the lungs. Whereas intrapulmonary TNF-alpha and IL-1beta production were associated with WT BM, levels of the CXC chemokines MIP-2 and KC as well as GM-CSF were associated with recipient genotype. We conclude that lung parenchymal and BM-derived cells collaborate in the MyD88-dependent response to P. aeruginosa infection in the lungs in mice.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Influence of sevoflurane on the metabolism and renal effects of compound A in rats.

BACKGROUND: The sevoflurane degradation product compound A is nephrotoxic in rats. In contrast, patient exposure to compound A during sevoflurane anesthesia has no clinically significant renal effects. The mechanism for this difference is incompletely understood. One possibility is that the metabolism and toxicity of compound A in humans is prevented by sevoflurane. However, the effect of sevoflurane on compound A metabolism and nephrotoxicity is unknown. Thus, the purpose of this investigation was to determine the effect of sevoflurane on the metabolism and renal toxicity of compound A in rats. METHODS: Male rats received 0.25 mmol/kg intraperitoneal compound A, alone and during sevoflurane anesthesia (3%, 1.3 minimum alveolar concentration, for 3 h). Compound A metabolites in urine were quantified, and renal function was evaluated by serum creatinine and urea nitrogen, urine volume, osmolality, protein excretion, and renal tubular histology. RESULTS: Sevoflurane coadministration with compound A inhibited compound A defluorination while increasing relative metabolism through pathways of sulfoxidation and beta-lyase-catalyzed metabolism, which mediate toxicity. Sevoflurane coadministration with compound A increased some (serum creatinine and urea nitrogen, and necrosis) but not other (urine volume, osmolality, and protein excretion) indices of renal toxicity. CONCLUSIONS: Sevoflurane does not suppress compound A nephrotoxicity in rats in vivo. These results do not suggest that lack of nephrotoxicity in surgical patients exposed to compound A during sevoflurane anesthesia results from an inhibitory effect of sevoflurane on compound A metabolism and toxicity. Rather, these results are consistent with differences between rats and humans in compound A exposure and inherent susceptibility to compound A nephrotoxicity.

Anesthetics, Inhalation↗

PubMed2005

The mSin3A chromatin-modifying complex is essential for embryogenesis and T-cell development.

The corepressor mSin3A is the core component of a chromatin-modifying complex that is recruited by multiple gene-specific transcriptional repressors. In order to understand the role of mSin3A during development, we generated constitutive germ line as well as conditional msin3A deletions. msin3A deletion in the developing mouse embryo results in lethality at the postimplantation stage, demonstrating that it is an essential gene. Blastocysts derived from preimplantation msin3A null embryos and mouse embryo fibroblasts (MEFs) lacking msin3A display a significant reduction in cell division. msin3A null MEFs also show mislocalization of the heterochromatin protein, HP1alpha, without alterations in global histone acetylation. Heterozygous msin3A(+/-) mice with a systemic twofold decrease in mSin3A protein develop splenomegaly as well as kidney disease indicative of a disruption of lymphocyte homeostasis. Conditional deletion of msin3A from developing T cells results in reduced thymic cellularity and a fivefold decrease in the number of cytotoxic (CD8) T cells, while helper (CD4) T cells are unaffected. We show that CD8 development is dependent on mSin3A at a step downstream of T-cell receptor signaling and that loss of mSin3A specifically decreases survival of double-positive and CD8 T cells. Thus, msin3A is a pleiotropic gene which, in addition to its role in cell cycle progression, is required for the development and homeostasis of cells in the lymphoid lineage.

Animals↗

PubMed2004

Respiratory epithelial cells regulate lung inflammation in response to inhaled endotoxin.

To determine the role of respiratory epithelial cells in the inflammatory response to inhaled endotoxin, we selectively inhibited NF-kappa B activation in the respiratory epithelium using a mutant I kappa B-alpha construct that functioned as a dominant negative inhibitor of NF-kappa B translocation (dnI kappa B-alpha). We developed two lines of transgenic mice in which expression of dnI kappa B-alpha was targeted to the distal airway epithelium using the human surfactant apoprotein C promoter. Transgene expression was localized to the epithelium of the terminal bronchioles and alveoli. After inhalation of LPS, nuclear translocation of NF-kappa B was evident in bronchiolar epithelium of nontransgenic but not of transgenic mice. This defect was associated with impaired neutrophilic lung inflammation 4 h after LPS challenge and diminished levels of TNF-alpha, IL-1 beta, macrophage inflammatory protein-2, and KC in lung homogenates. Expression of TNF-alpha within bronchiolar epithelial cells and of VCAM-1 within peribronchiolar endothelial cells was reduced in transgenic animals. Thus targeted inhibition of NF-kappa B activation in distal airway epithelial cells impaired the inflammatory response to inhaled LPS. These data provide causal evidence that distal airway epithelial cells and the signals they transduce play a physiological role in lung inflammation in vivo.

Administration, Inhalation↗

PubMed2004

Cutting edge: myeloid differentiation factor 88 is essential for pulmonary host defense against Pseudomonas aeruginosa but not Staphylococcus aureus.

Myeloid differentiation factor 88 (MyD88) is an adapter molecule required for signal transduction via Toll-like receptors (TLRs) and receptors of the IL-1 family. Consequently, MyD88-deficient mice are highly susceptible to bacterial infections, including systemic infection with Staphylococcus aureus. To determine the role of MyD88 in innate immunity to bacterial pneumonia, we exposed MyD88-deficient and wild-type mice to aerosolized Pseudomonas aeruginosa or S. aureus. As predicted, MyD88-deficient mice failed to mount an early cytokine or inflammatory response or to control bacterial replication after infection with P. aeruginosa, which resulted in necrotizing pneumonia and death. By contrast, MyD88-deficient mice controlled S. aureus infection despite blunted local cytokine and inflammatory responses. Thus, whereas MyD88-dependent signaling is integral to the initiation of cytokine and inflammatory responses to both pathogens following infection of the lower respiratory tract, MyD88 is essential for innate immunity to P. aeruginosa but not S. aureus.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Role of cytochrome P4503A in cysteine S-conjugates sulfoxidation and the nephrotoxicity of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A) in rats.

The volatile anesthetic sevoflurane is degraded to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) in anesthesia machines. FDVE is nephrotoxic in rats. FDVE undergoes glutathione conjugation, subsequent conversion to cysteine and mercapturic acid conjugates, and cysteine conjugate metabolism by renal beta-lyase, which is a bioactivation pathway mediating nephrotoxicity in rats. Recent in vitro studies revealed cytochrome P4503A-catalyzed formation of novel sulfoxide metabolites of FDVE cysteine-S and mercapturic acid conjugates in rat liver and kidney microsomes. FDVE-mercapturic acid sulfoxides were more toxic than other FDVE conjugates to renal proximal tubular cells in culture. Nevertheless, the occurrence and toxicological significance of FDVE sulfoxides formation in vivo remain unknown. This investigation determined, in rats in vivo, the existence, role of P4503A, and nephrotoxic consequence of FDVE conjugates sulfoxidation. Rats were pretreated with dexamethasone, phenobarbital, troleandomycin, or nothing (controls) before FDVE, and then, nephrotoxicity, FDVE-mercapturate sulfoxide urinary excretion, and FDVE-mercapturate sulfoxidation by liver microsomes were assessed. The formation of FDVE-mercapturic acid sulfoxide metabolites in vivo and their urinary excretion were unambiguously established by mass spectrometry. Dexamethasone and phenobarbital increased, and troleandomycin decreased (i) liver microsomal FDVE-mercapturic acid sulfoxidation in vitro, (ii) FDVE-mercapturic acid sulfoxide urinary excretion in vivo, and (iii) FDVE nephrotoxicity in vivo assessed by renal histology, blood urea nitrogen concentrations, and urine volume and protein excretion. Urine 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, reflecting beta-lyase-dependent FDVE-cysteine S-conjugates metabolism, was minimally affected by the pretreatments. These results demonstrate that FDVE S-conjugates undergo P4503A-catalyzed sulfoxidation in rats in vivo, and this sulfoxidation pathway contributes to nephrotoxicity. FDVE S-conjugates sulfoxidation constitutes a newly discovered mechanism of FDVE bioactivation and toxicification in rats, in addition to beta-lyase-catalyzed metabolism of FDVE-cysteine S-conjugates.

Anesthetics, Inhalation↗

PubMed2003

Sustained tolerance to lipopolysaccharide after liver ischemia-reperfusion injury.

Liver ischemia-reperfusion injury (IR) would be expected to alter the capacity of previously ischemic as well as continuously perfused segments that are exposed to circulating inflammatory mediators to respond to a subsequent infectious insult. IR is reported to induce tolerance to subsequent endotoxin stimulation if the lipopolysaccharide (LPS) challenge is delayed until the late, neutrophil-mediated phase of reperfusion. Whether ischemic or perfused liver is differentially affected and whether LPS-tolerance may be overcome by increasing exposure is unknown. We hypothesized that late tolerance after IR reflects a refractory state in which the liver's expression of pro-inflammatory mediators in response to secondary LPS is limited. Precision-cut tissue culture methodology was used to investigate the capacity of rabbit liver to respond to a spectrum of LPS stimulation 24 h after partial IR. Slices from normal liver showed a dose-dependent response to LPS for tumor necrosis factor (TNF-alpha) expression. Slices from both previously ischemic and continuously perfused lobes retained dose responsiveness for TNF-alpha, although TNF-alpha was significantly decreased at high LPS concentrations compared with normal liver. Ischemic liver sustained this blunted response despite extended exposure to LPS, whereas perfused slices recovered responsiveness to high dose LPS with prolonged stimulation. IR induced interleukin-8 in both ischemic and perfused liver, but secondary LPS stimulation did not augment interleukin-8 expression. Hepatic IR induces a late tolerance to secondary LPS challenge in locally ischemic tissue that cannot be overcome by increasing LPS exposure. Nonischemic liver exposed to the systemic effects of IR injury, however, retains a capacity to respond to LPS with sufficient stimulation.

Animals↗

PubMed2002

The gastrin receptor promotes pancreatic growth in transgenic mice.

INTRODUCTION: We demonstrated previously, in two different rodent models of pancreatic cancer, that the gastrin receptor is present on malignant pancreatic tumors in spite of the fact that the normal adult rat and mouse pancreas does not express gastrin receptors. AIMS AND METHODOLOGY: To determine whether gastrin receptors mediate pancreatic growth or promote carcinogenesis or both, we created a transgenic mouse that constitutively expresses gastrin receptors in the exocrine pancreas. The transgene construct contained the full-length rat gastrin receptor cDNA sequence under the control of the rat elastase promoter. RESULTS: Receptor presence and function on exocrine pancreatic tissue of transgenic but not control mice were confirmed by (125)I-gastrin-I binding studies and by gastrin stimulation of intracellular calcium release. Eighteen-month-old transgenic animals had larger pancreas-to-body weight ratios than their nontransgenic littermate controls (p < 0.001 for females; p < 0.01 for males); however, histopathologic examination revealed no neoplasms or other abnormalities. CONCLUSION: In both female and male transgenic mice, the expression of the gastrin receptor in the exocrine pancreas is associated with a significant increase in pancreas weight, but it does not appear to promote the development of spontaneous pancreatic tumors.

Adenocarcinoma↗

PubMed2001

Strain-based genetic differences regulate the efficiency of systemic gene delivery as well as expression.

We have characterized the impact of strain-based genetic differences on the efficiency of the intravenous cationic liposome-DNA complex (CLDC)-based gene transfer and expression in mice. We also investigated what steps in the gene delivery and expression pathway appeared responsible for these strain-related differences and whether such differences could be compensated for either by agents that alter host pathways important in CLDC-mediated gene transfer and expression, or by changes in CLDC formulation. We found that different mouse strains can exhibit different expression levels and/or differences in the amount of plasmid DNA delivered to the organs where the DNA is expressed. Furthermore, drug pretreatment or reformulation of the CLDC could improve DNA delivery and/or gene expression in a strain-specific fashion. We conclude that genetic factors critically modify both the tissue deposition and the expression of genetic materials delivered by CLDC. Because manipulation of either the host or the CLDC could at least partially compensate for these strain-related differences, such strategies may be required to effectively use non-viral gene transfer approaches in genetically diverse populations.

Animals↗