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PubMed1999

Repeated administration of adenoviral vectors in lungs of human CD4 transgenic mice treated with a nondepleting CD4 antibody.

The central role of CD4+ T cells in regulation of adenovirus vector-mediated immune responses has been documented previously in murine models. We analyzed the effects of a nondepleting mAb to human CD4 (CD4 mAb; Clenoliximab) on immune functions following intratracheal administration of adenoviral vectors in murine CD4-deficient mice (muCD4KO) expressing a human CD4 transgene (HuCD4 mice). Treatment of HuCD4 mice with Clenoliximab inhibited both cell-mediated and humoral immune responses to adenoviral Ags. Chronic treatment of HuCD4 mice with Clenoliximab permitted successful readministration of adenoviral vectors at least four times. The ability to readminister these vectors is associated with marked suppression of neutralizing Ab responses to viral capsid proteins. Clenoliximab also inhibited CTL and prolonged expression of the transgene. T or B cell responses to adenovirus did not emerge after the effects of a short course of Clenoliximab diminished. These data illustrate the potential utility of a nondepleting CD4 Ab in facilitating gene therapy using adenoviral vectors.

Adenoviridae↗
PubMed2002

Comparison of protein phosphatase inhibitory activity and apparent toxicity of microcystins and related compounds.

Two metabolites of microcystin-LR glutathione conjugate and, microcystin-cysteine conjugate, as well as microcystin-RR (MCRR) are less toxic than microcystin-LR (MCLR). In the present study, we investigated why these compounds are weakly toxic in comparison with MCLR, as the reason is still unknown and no systematic study has so far been carried out for a clarification of this issue. Although they showed almost the same inhibitory activity against protein phosphatases 1 and 2A as MCLR in vitro, the apparent toxicity of these three compounds by intratracheal administration to mice decreased to about 1/12 the level of MCLR at 100microg/kg. An immunostaining study showed that these conjugates at a sublethal dose of 200microg/kg were prominently observed in the intestine and kidney, whereas effective accumulation and bleeding were not found in the liver in spite of the larger dosage. As an explanation for these results, there may be two possibilities. First, the transport system to the liver might not function well, and second, transported toxins may be effectively eliminated by an appropriate system such as the GS-X (ATP-dependent glutathione S-conjugate exported) pump. It was concluded that the inhibitory activity against protein phosphatases is not always related to the apparent LD(50) level, and that the appearance of toxicity by microcystins depends on the balance between accumulation and metabolism in the liver.

Animals↗
PubMed1989

The hamster model of chronic Mycobacterium avium complex infection.

Male golden Syrian hamsters were evaluated as a model for the pathogenesis of human infection with Mycobacterium avium complex. Intratracheal inoculation produced a chronic, nonfatal, pulmonary and disseminated infection (overall rate, 86%). The frequency of infection in hamsters that received 5 x 10(8) versus 1 x 10(8) colony forming units (cfu) was not significantly different (87% and 92%, respectively), but 1 x 10(7) cfu produced infection in only 78% of inoculated animals (P = .034). The percentage of animals developing pulmonary infection with M. avium complex did not differ between inoculum groups (77%-80%). Disseminated infection occurred significantly less frequently in the 1 x 10(7) group (46%) compared with the 5 x 10(8) (79%) and 1 x 10(8) (68%) groups (P = .001 and .056, respectively). After seven weeks, partial clearance of M. avium complex from the lungs coincided with an increased number of animals with splenic involvement. The hamster may be a useful model for human infection with M. avium complex.

Animals↗
PubMed2000

Endotracheal surfactant atomization: an alternative to bolus instillation?

OBJECTIVE: To investigate the effect of an intratracheal surfactant fog on oxygenation, blood pressure, distribution, and recovery rate as a pilot study to intratracheal surfactant aerosol. DESIGN: Prospective, randomized study. SETTING: University laboratory. SUBJECTS: A total of 15 New Zealand White rabbits. INTERVENTIONS: The anesthetized ventilated rabbits were surfactant-deprived by repeated lung lavages and then received 200 mg/kg of a 99mTc-labeled porcine surfactant (Curosurf) either as bolus or as intratracheal surfactant fog. MEASUREMENTS AND MAIN RESULTS: Blood gases and pressure were measured and distribution as well as recovery rate of the surfactant determined by means of the radio label (gamma camera images and lung processing with subsequent gamma counter measurements). Respiratory function normalized immediately, no difference could be found between the two groups with regard to PaO2, PaCO2, and blood pressure. Even distribution of the radiolabel was found with both methods, the bolus group showing a higher percentage of lung pieces with label concentrations of double average or more. Recovery rates were 82.5%+/-13.1% (mean +/- SD) in the bolus group and 86.5%+/-7.7% in the fog group. CONCLUSION: Endotracheal surfactant fog application is as effective as bolus instillation and may have a role in the treatment of adult respiratory distress syndrome. It has to be considered as a first step in producing an effective aerosol.

Aerosols↗
PubMed2003

Alveolar macrophage apoptosis contributes to pneumococcal clearance in a resolving model of pulmonary infection.

The role of alveolar macrophages (AM) in host defense against pulmonary infection has been difficult to establish using in vivo models. This may reflect a reliance on models of fulminant infection. To establish a unique model of resolving infection, with which to address the function of AM, C57BL/6 mice received low-dose intratracheal administration of pneumococci. Administration of low doses of pneumococci produced a resolving model of pulmonary infection characterized by clearance of bacteria without features of pneumonia. AM depletion in this model significantly increased bacterial outgrowth in the lung. Interestingly, a significant increase in the number of apoptotic AM was noted with the low-dose infection as compared with mock infection. Caspase inhibition in this model decreased AM apoptosis and increased the number of bacteremic mice, indicating a novel role for caspase activation in pulmonary innate defense against pneumococci. These results suggest that AM play a key role in clearance of bacteria from the lung during subclinical infection and that induction of AM apoptosis contributes to the microbiologic host defense against pneumococci.

Amino Acid Chloromethyl Ketones↗
PubMed1998

Respiratory work in elastase treated hamsters.

Biomechanical adaptations of the diaphragm in the hamster model of emphysema are similar to those observed in skeletal muscle with exercise training. The aim of this study was to evaluate whether the dynamic pressure-volume (PV) work of breathing in hamsters with elastase-induced emphysema may contribute to these adaptations. PV work in elastase treated animals was compared to healthy controls. The studies were performed in adult hamsters 14-16 months following intratracheal administration of elastase (elastase treated group, ET) or saline (control group, CTL). Airway and esophageal pressures and air flows were measured during spontaneous breathing in anesthetized, supine animals. Pulmonary work (WL) was computed from transpulmonary pressures and airflows. Functional residual capacity (FRC) and total lung capacity (TLC; defined as volume at 25 cmH2O) in ET were increased 2 and 1.8 times, respectively, compared with CTL. Averaged tidal volume (VT) and inspiratory flows were comparable between groups. Total work of breathing (WT) normalized per ml VT was not significantly affected with elastase treatment but the pulmonary elastance work (WE) was significantly less in ET animals than controls (0.88 +/- 0.61 g cm(-2) vs. 1.63 +/- 0.32). Pulmonary resistive work was not significantly different between ET and CTL animals. These results suggest that biomechanical adaptations of the diaphragm observed in ET hamsters are caused by mechanisms other than the changes in dynamic mechanical properties of the lung following elastase treatment.

Animals↗
PubMed1987

The immunological consequences of challenge with bovine tubercle bacilli in badgers (Meles meles).

Optimal conditions were determined for performing antibody measurements (ELISA), lymphocyte transformation tests and, to some extent, skin tests in badgers. These parameters, together with the bacteriological and pathological studies reported previously (Pritchard et al. 1987), were used to follow the course of intradermal and intratracheal challenge of badgers with bovine tubercle bacilli. Two challenge doses were used for each route of infection and two animals received each dose. None of the four animals challenged by the intratracheal method showed any evidence of infection, suggesting that adult badgers may have some resistance to challenge by this method. All four animals challenged intradermally developed lesion of tuberculosis. Immunologically the disease passed through three phases. There was an early phase in which lymphocyte transformation to whole BCG steadily and significantly increased, and skin tests to tuberculin became positive but there was little change in antibody levels. This was followed by an intermediate phase of variable skin responses, fluctuating lymphocyte transformation and significant increase in antibody levels. The final phase, which was only seen in two animals with extensive disease, was associated with changing skin reactions and falling lymphocyte responses, together with a sudden increase in antibody levels. This paper presents the first formal evidence of cell-mediated immunity to tuberculosis in the badger, which may delay onset and prolong the survival of challenged animals.

Animals↗
PubMed2000

Oil fly ash-induced elevation of plasma fibrinogen levels in rats.

Particulate matter air pollution (PM) has been associated with morbidity and mortality from ischemic heart disease and stroke in humans. It has been hypothesized that alveolar inflammation, resulting from exposure to PM, may induce a state of blood hypercoagulability, triggering cardiovascular events in susceptible individuals. Previous studies in our laboratory have demonstrated acute lung injury with alveolar inflammation in rats following exposure to residual oil fly ash (ROFA), an emission source particulate. In addition, increased mortality has been documented following exposure to ROFA in rats with preexistent cardiopulmonary disease. ROFA's toxicity derives from its soluble metal content, which appears also to drive the toxicity of ambient PM. The present study was conducted to test the hypothesis that exposure of rats to a toxic PM, like ROFA, would adversely alter hemostatic parameters and cardiovascular risk factors thought to be involved in human epidemiologic findings. Sixty-day-old male Sprague-Dawley rats were exposed by intratracheal instillation (IT) to varying doses (0.3, 1. 7, or 8.3 mg/kg) of ROFA, 8.3 mg/kg Mt. Saint Helen's volcanic ash (MSH, control particle), or 0.3 ml saline (SAL, control). At 24 h post-IT, activated partial thromboplastin time (APTT), prothrombin time (PT), plasma fibrinogen (PF), plasma viscosity (PV), and complete blood count (CBC) were performed on venous blood samples. No differences from control were detected in APTT and PT in ROFA-exposed rats; however, ROFA exposure did result in elevated PF, at 8.3 mg/kg only. In addition, PV values were elevated in both ROFA and MSH-exposed rats relative to SAL-control rats, but not significantly. Although no changes were detected in APTT and PT, alteration of important hematologic parameters (notably fibrinogen) through PM induction of an inflammatory response may serve as biomarkers of cardiovascular risk in susceptible individuals.

Air Pollutants↗
PubMed2002

Mutagenicity and in vivo toxicity of combined particulate and semivolatile organic fractions of gasoline and diesel engine emissions.

Exposure to engine emissions is associated with adverse health effects. However, little is known about the relative effects of emissions produced by different operating conditions, fuels, or technologies. Rapid screening techniques are needed to compare the biological effects of emissions with different characteristics. Here, we examined a set of engine emission samples using conventional bioassays. The samples included combined particulate material and semivolatile organic compound fractions of emissions collected from normal- and high-emitter gasoline and diesel vehicles collected at 72 degrees F, and from normal-emitter groups collected at 30 degrees F. The relative potency of the samples was determined by statistical analysis of the dose-response curves. All samples induced bacterial mutagenicity, with a 10-fold range of potency among the samples. Responses to intratracheal instillation in rats indicated generally parallel rankings of the samples by multiple endpoints reflecting cytotoxic, inflammatory, and lung parenchymal changes, allowing selection of a more limited set of parameters for future studies. The parameters selected to assess oxidative stress and macrophage function yielded little useful information. Responses to instillation indicated little difference in potency per unit of combined particulate material and semivolatile organic compound mass between normal-emitter gasoline and diesel vehicles, or between emissions collected at different temperatures. However, equivalent masses of emissions from high-emitter vehicles of both types were more potent than those from normal-emitters. While preliminary in terms of assessing contributions of different emissions to health hazards, the results indicate that a subset of this panel of assays will be useful in providing rapid, cost-effective feedback on the biological impact of modified technology.

Air Pollutants↗
PubMed2003

Signal transduction events in lung injury induced by 2-chloroethyl ethyl sulfide, a mustard analog.

Sulfur mustard has been used as a vesicant chemical warfare agent. To understand the mechanism by which mustard gas exposure causes respiratory damage, we have used 2-chloroethyl ethyl sulfide (CEES) as a mustard analog. Our initial studies have shown that guinea pigs exposed to CEES intratracheally accumulate high levels of TNF-alpha. Accumulation of TNF-alpha leads to activation of both acid and neutral sphingomyelinases, resulting in high accumulation of ceramides, a second messenger involved in cell apoptosis. In addition, NF-kappa B was activated for a short period (1-2 h after exposure) as determined by mobility shift assay. Supershift assays indicated that both p50 and p65 of NF-kappa B were activated due to CEES exposure. However, NF-kappa B rapidly disappeared after 2 h. It is possible that the initial activation of NF-kappa B was an adaptive response to protect the cells from damage since NF-kappa B is known to inhibit TNF-alpha/ceramide-induced cell apoptosis. Since NF-kappa B disappeared after 2 h, the cells continued being damaged owing to accumulation of ceramides and activation of several caspases, leading to apoptosis.

Administration, Inhalation↗
PubMed1997

Bleomycin induces strain-dependent alterations in the pattern of epithelial cell-specific marker expression in mouse lung.

Clinical use of the antineoplastic agent bleomycin is restricted due to pulmonary toxicity. Murine models of bleomycin-induced pulmonary fibrosis have been developed in an attempt to understand the mechanisms involved in the fibrotic process. Studies have shown that the alveolar epithelium is damaged early after bleomycin treatment. The purpose of this study was to evaluate the pattern of gene expression in airway and alveolar epithelial cells after bleomycin exposure in mice that vary in susceptibility to bleomycin-induced fibrosis. Surfactant protein C (SPC) and Clara cell-specific protein (CC10) mRNA were used as cell-specific markers of alveolar type II cells and airway Clara cells, respectively. Mice were treated with a single intratracheal dose of bleomycin and the pattern of SPC and CC10 transcripts was examined by in situ hybridization. The pattern of SPC mRNA 28 days after treatment was uniform in controls and resistant mice but exhibited a patchy appearance in sensitive mice. Bleomycin treatment also resulted in a strain-dependent loss of CC10 mRNA-expressing cells. In sensitive mice 28 days after treatment, SPC mRNA was ectopically expressed in the distal bronchiolar epithelium in a morphologically distinct cell type. Serial sections revealed that these cells either coexpressed CC10 mRNA or were located adjacent to CC10 mRNA-containing cells. This unique cell population may represent a progenitor cell type important in epithelial repair. The strain-dependent changes in CC10 and SPC gene expression after bleomycin treatment are suggestive of a role for the epithelium in pulmonary fibrosis versus repair.

Animals↗
PubMed2001

Effects of gadolinium on the retention and translocation of 239Pu-hydroxide.

The effect of gadolinium on the lung retention, excretion, and translocation of plutonium was studied in rats instilled intratracheally with plutonium hydroxide with and without gadolinium. Three types of plutonium hydroxide were prepared: pure 239Pu-hydroxide colloid, that containing a high concentration of gadolinium, and that containing a low concentration of gadolinium. The lung retention of 239Pu was higher and the fecal excretion was lower in the rats administered 239Pu-hydroxide containing a high concentration of gadolinium than those administered pure 239Pu-hydroxide colloid. The translocation of 239Pu from lung to other organs including the liver, spleen, femur, and kidney was not affected by gadolinium. The cytological examination of bronchoalveolar lavage cells showed that the administration of 239Pu-hydroxide containing a high concentration of gadolinium induced the inflammatory reactions in the lung. The delayed alveolar clearance of plutonium in the rats administered 239Pu-hydroxide colloid containing a high concentration of gadolinium may be attributable to the change in physicochemical characteristics of colloid and the inflammation induced in the lung by gadolinium.

Animals↗
PubMed2005

Exaggerated airway narrowing in mice treated with intratracheal cationic protein.

Airway hyperresponsiveness in mice with allergic airway inflammation can be attributed entirely to exaggerated closure of peripheral airways (Wagers S, Lundblad LK, Ekman M, Irvin CG, and Bates JHT. J Appl Physiol 96: 2019-2027, 2004). However, clinical asthma can be characterized by hyperresponsiveness of the central airways as well as the lung periphery. We, therefore, sought to establish a complementary model of hyperresponsiveness in the mouse due to excessive narrowing of the airways. We treated mice with a tracheal instillation of the cationic protein poly-l-lysine (PLL), hypothesizing that this would reduce the barrier function of the epithelium and thereby render the underlying airway smooth muscle more accessible to aerosolized methacholine. The PLL-treated animals were hypersensitive to methacholine: they exhibited an exaggerated response to submaximal doses but had a maximal response that was similar to controls. With the aid of a computational model of the mouse lung, we conclude that the methacholine responsiveness of PLL-treated mice is fundamentally different in nature to the hyperresponsiveness that we found previously in mice with allergically inflamed lungs.

Administration, Inhalation↗
PubMed2000

Mucosal IL-12 inhibits airway reactivity to methacholine and respiratory failure in murine asthma.

The worldwide incidence, prevalence, and fatality rates from asthma are increasing despite currently available therapeutic modalities. Systemic administration of interleukin (IL)-12 has been shown to inhibit airway reactivity in murine models of asthma, but the required dosage is high and may be toxic. This study tested the hypothesis that IL-12 administered directly into the lungs is more effective in inhibiting airway reactivity than systemically administered IL-12, allowing lower doses to be used. A low dose (10 ng) of IL-12 was delivered either intratracheally (mucosal delivery) or intraperitoneally (systemic delivery) at the time of ragweed (RW) challenge in mice sensitized to RW. Basal airway resistance and airway reactivity to methacholine were measured 3 days after RW challenge. Compared to phosphate-buffered saline (PBS) challenge of RW sensitized mice, RW challenge increased basal resistance and the slope of the methacholine dose-response curve. Methacholine challenge of RW-challenged mice also induced premature respiratory failure (respiratory rate < 150/min, tidal volume < 0.15 mL) in some animals. Administration of mucosal or systemic IL-12 at the time of RW challenge decreased basal airway resistance. However, only mucosal IL-12 decreased airway reactivity and inhibited respiratory failure during methacholine challenge. These findings indicate that mucosal delivery of a low dose of IL-12 is more effective than systemic IL-12 in inhibiting airway reactivity and respiratory failure in a mouse model of asthma.

Adjuvants, Immunologic↗
PubMed1986

Effect of intratracheally administered anticancer drugs on lung hydroxyproline content.

The systemic administration of the anticancer drug bleomycin is associated with the development of lung damage and fibrosis. Intratracheal (i.t.) instillation of bleomycin has often been employed in animal models of this lesion to more rapidly elicit lung damage. However, various drugs and chemicals are known to induce lung damage and fibrosis when given i.t. The results presented here demonstrate that, in addition to bleomycin, the i.t. instillation of dactinomycin, mitomycin c, doxorubicin, and cyclophosphamide resulted in increased lung levels of hydroxyproline, an indicator of fibrosis. In contrast, increases were not seen following i.t. doses of 5-fluorouracil or vincristine, and 1,3-bis(2-chloroethyl)-1-nitrosourea(BCNU) actually decreased lung hydroxyproline content. These findings suggest that i.t. treatments with bleomycin may produce lung damage more representative of anticancer drugs in general than the specific lesion which is produced when bleomycin is administered systemically. The mechanisms underlying i.t. drug-induced increases in lung hydroxyproline are not known, but may be related to the ability of cell-cycle-nonspecific anticancer drugs to directly damage alveolar epithelial cells.

Animals↗
PubMed2003

Pulmonary toxicity studies in rats with triethoxyoctylsilane (OTES)-coated, pigment-grade titanium dioxide particles: bridging studies to predict inhalation hazard.

The aim of this study was to assess and compare the acute lung toxicities of intratracheally instilled hydrophobic relative to hydrophilic surface-coated titanium dioxide (TiO(2)) particles using a pulmonary bridging methodology. In addition, the results of these instillation studies were bridged with data previously generated from inhalation studies with hydrophilic, pigment-grade (base) TiO(2) particles, using the base, pigment-grade TiO(2) particles as the inhalation/instillation bridge material. To conduct toxicity comparisons, the surface coatings of base pigment-grade TiO(2) particles were made hydrophobic by application of triethoxyoctylsilane (OTES), a commercial product used in plastics applications. For the bioassay experimental design, rats were intratracheally instilled with 2 or 10 mg/kg of the following TiO(2) particle-types: (1) base (hydrophilic) TiO(2) particles; (2) TiO(2) with OTES surface coating; (3) base TiO(2) with Tween 80; or (4) OTES TiO(2) with Tween 80. Saline instilled rats served as controls. Following exposures, the lungs of sham- and TiO(2)-exposed rats were assessed both using bronchoalveolar lavage (BAL) biomarkers and by histopathology of lung tissue at 24 hours, 1 week, 1 month, and 3 months post exposure. The results demonstrated that only the base, high-dose (10 mg/kg) pigment-grade TiO(2) particles and those with particle-types containing Tween 80 produced a transient pulmonary inflammatory response, and this was reversible within 1 week postexposure. The authors conclude that the OTES hydrophobic coating on the pigment-grade TiO(2) particle does not cause significant pulmonary toxicity.

Animals↗
PubMed1998

Ultrasonic nebulization of cationic lipid-based gene delivery systems for airway administration.

PURPOSE: This study relates to the development of gene therapies for the treatment of lung diseases. It describes for the first time the use of ultrasonic nebulization for administration of plasmid/lipid complexes to the lungs to transfect lung epithelial cells. METHODS: Plasmid complexed to cationic liposomes at a specific stoichiometric ratio was nebulized using an ultrasonic nebulizer. We assessed: (i) the stability of plasmid and plasmid/lipid complexes to ultrasonic nebulization, (ii) the in vitro activity of plasmid in previously nebulized plasmid/lipid complex, (iii) the in vivo transgene expression in lungs following intratracheal instillation of nebulized plasmid/lipid formulations compared to un-nebulized complexes, (iv) the emitted dose from an ultrasonic nebulizer using plasmid/lipid complexes of different size, and (v) the transgene expression in lungs following oral inhalation of aerosolized plasmid/lipid complex generated using an ultrasonic nebulizer. RESULTS: Integrity of plasmid formulated with cationic lipids, and colloidal stability of the plasmid/lipid complex were maintained during nebulization. In contrast, plasmid alone formulated in 10% lactose was fragmented during nebulization. The efficiency of transfection of the complex before and after nebulization was comparable. Nebulization produced respirable aerosol particles. Oral exposure of rodents for 10 minutes to aerosol produced from the ultrasonic nebulizer resulted in transgene expression in lungs in vivo. CONCLUSIONS: The performance characteristics of the ultrasonic nebulizer with our optimized plasmid/lipid formulations suggests that this device can potentially be used for administering gene medicines to the airways in clinical settings for the treatment of respiratory disorders.

Aerosols↗
PubMed2004

Application of novel solid lipid nanoparticle (SLN)-gene vector formulations based on a dimeric HIV-1 TAT-peptide in vitro and in vivo.

PURPOSE: To optimize gene delivery of SLN-based gene vectors by incorporation of a dimeric HIV-1 TAT peptide (TAT2) into SLN gene vectors. METHODS: Plasmid DNA was complexed with two SLN preparations either with or without pre-compaction of DNA by TAT2, poly-L-arginine, or the mutant TAT2-M1. DNA complexed with polyethylenimine (PEI) served as a standard. Gene expression was analyzed upon transfection of bronchial epithelial cells in vitro and after intratracheal instillation or aerosol application to the lungs of mice in vivo. Stability of DNA was analyzed by agarose gel electrophoresis. RESULTS: Incorporation of TAT2 into SLN gene vectors induced an up to 100-fold sequence-dependent increase of gene expression as compared with the mutant TAT2-M1 and was 4- to 8-times higher as compared with PEI in vitro. In vivo application of TAT2-SLN gene vectors via jet nebulization increased SLN-based gene expression but was accompanied with DNA degradation. DNA degradation was not observed when an innovative device operating on the principle of a perforated vibrating membrane was used. CONCLUSIONS: Incorporation of TAT2 into SLN gene vectors is suitable to optimize gene transfer in vitro. The use of a mild nebulization technology avoids DNA degradation and offers the opportunity for further studies in large animal models.

Aerosols↗