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PubMed1986

The toxic effect of diquat on the rat lung after intratracheal administration.

Diquat toxicity to the lung was evaluated in rats. Diquat was administered intratracheally (i.t.) and its toxic potential was compared with that of paraquat. Diquat showed toxic effects in the lung when administered i.t. In previous research, diquat administered by the intravenous (i.v.) or oral (p.o.) route had little effect on the lung. a sufficient dose of diquat administered i.t. would be potentially toxic to the lung, but diquat is much less toxic to the lung than paraquat, which is actively taken up by lung tissue. This suggests that diquat is not actively taken up by lung tissue when administered i.t., but may be passively taken up by the lung tissue and induce lung damage.

Animals↗

PubMed1998

Route dependent pulmonary first-pass metabolism of a series of biphenylacetic acid esters in rats.

The influence of route of administration of a series of biphenylacetic acid aliphatic esters on their pulmonary first-pass metabolism in rats was investigated. The results were compared with in vitro data and with the physicochemical properties of the esters. Pre- and post-absorptive first-pass metabolism was assessed by comparing area under blood concentration-time curves after intra-arterial administration of the esters with those seen after intravenous (to assess post-absorptive) and intratracheal (to assess pre-absorptive) administration. The extent of pulmonary metabolism was dependent on the route of administration. For all the esters studied there was insignificant post-absorptive first-pass extraction, however there was a large pre-absorptive first-pass extraction (greater than 80%). Enzyme kinetics derived in vitro using the 'well-stirred' model (Dickinson and Taylor, 1995. Int. J. Pharm. 116, 231-236) predicted the extent of post-absorptive but not the pre-absorptive, first-pass metabolism.

Animals↗

PubMed2000

Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations.

The evaluation of respiratory tract toxicity from airborne materials frequently involves exposure of animals via inhalation. This provides a natural route of entry into the host and, as such, is the preferred method for the introduction of toxicants into the lungs. However, for various reasons, this technique cannot always be used, and the direct instillation of a test material into the lungs via the trachea has been employed in many studies as an alternative exposure procedure. Intratracheal instillation has become sufficiently widely used that the Inhalation Specialty Section of the Society of Toxicology elected to develop this document to summarize some key issues concerning the use of this exposure procedure. Although there are distinct differences in the distribution, clearance, and retention of materials when administered by instillation compared to inhalation, the former can be a useful and cost-effective procedure for addressing specific questions regarding the respiratory toxicity of chemicals, as long as certain caveats are clearly understood and certain guidelines are carefully followed.

Aerosols↗

PubMedDate not supplied

[Content of trace elements and steroid hormones in blood and tissues of internal organs in experimental pulmonary fibrosis induced by intratracheal administration of bleomycetin].

Pulmonary fibrosis was produced in rats by intratracheal administration of bleomycetin. The development of the fibrous process in the lungs was attended by marked reduction of the zinc content in the tissues of the viscera, plasma, and formed elements of the blood, as well as of corticosterone and testosterone in blood plasma. Respiratory insufficiency is a probable cause of the developing zinc-deficiency which leads to disturbed synthesis of steroid hormones. Injection of exogenous testosterone normalizes partly the level of steroid hormones in the blood, improves the general condition of the animals, and facilitates an increase of body weight.

Animals↗

PubMed1996

Effect of nordihydroguaiaretic acid and ibuprofen on bleomycin and hyperoxia-induced changes in lung superoxide dismutase, prostaglandins and lethality.

Mortality in hamsters injected intratracheally with bleomycin (bleo) (0.25 units) and exposed to 70% oxygen is significantly increased over 14 days when they receive nordihydroguaiaretic acid (NDGA, 10 mg/kg per day S.C.). Mortality in bleo +O2 challenged hamsters treated with ibuprofen (10 mg/kg per day) subcutaneously was not significantly increased. The increased mortality in NDGA treated animals is not the result of augmented superoxide formation, since no change in lung superoxide dismutase occurred. Among the prostaglandins measured, NDGA produced the greatest elevation in 6-keto-PGF1 alpha (stable product of prostacyclin) and thromboxane B2 (stable product of thromboxane A2).

Animals↗

PubMed2006

Translocation pathway of the intratracheally instilled ultrafine particles from the lung into the blood circulation in the mouse.

Recently, it has been demonstrated that ultrafine particles (UFPs) are able to translocate from the lung into the systemic circulation. Precise mechanisms of the anatomical translocation (crossing the air-blood barrier) of inhaled UFPs at the alveolar wall are not fully understood. In this study, we examined the translocation pathway of the intratracheally instilled ultrafine carbon black (UFCB) from the lung into the blood circulation in mouse. Electron microscopy demonstrated accumulation of intratracheally instilled UFCB in the large-sized gaps developing between the cytoplasmic processes of the alveolar epithelial cells, possibly as a result of shrinkage of cytoplasm, by receiving stimulus/signals generated and released following UFCB attachment on the alveolar epithelial cells. Occasional penetration of the accumulated UFCB into the alveolar basement membrane, exposing to the air space, was observed at the gap. These results suggest that inhaled UFPs may, in part, pass the air-blood barrier through the large-sized gap formed between the alveolar epithelial cells.

Animals↗

PubMed2001

Extended lung expression and increased tissue localization of viral IL-10 with adenoviral gene therapy.

IL-10 is a pleiotropic cytokine that acts as an important regulator of macrophage, T cell, and natural killer cell functions. Human IL-10 (hIL-10) has both stimulatory and inhibitory effects on a wide variety of cell types. Viral IL-10 (vIL-10) possesses only a subset of hIL-10's activities, predominantly its suppression of cytokine synthesis by T helper type 1 clones. In the present report, we evaluated tissue accumulation and biological activity of hIL-10 and vIL-10 in vivo in individual organs by using a first-generation adenoviral (Ad) vector administered intratracheally and intravenously. We report the observation that Ad vectors delivering vIL-10, but not hIL-10, are associated with prolonged expression in the lung (>42 days) when delivered intratracheally. In contrast, there was no prolongation in vIL-10 expression when Ad vectors were intravenously administered, although vIL-10 levels in the tissue, but not serum, were markedly increased relative to hIL-10. Moreover, we report an augmented capacity of expressed vIL-10 versus hIL-10 to suppress the acute inflammatory responses in the lung to intratracheal administration of Ad. These findings confirm fundamental differences in Ad-induced expression of vIL-10 and hIL-10 when administered to the lungs. The results further suggest that Ad vectors expressing vIL-10 may have a role as anti-inflammatory agents in the treatment of acute and chronic lung inflammation.

Adenoviridae↗

PubMed1989

[The effectiveness of intratracheal antibiotic administration. Clinical, microbiologic and pharmacologic results].

In 199 artificially ventilated patients of an internal intensive care unit clinical, bacteriological and pharmacological effects of endotracheally administered gentamicin were investigated. The dose schedule was 2-4 x 40 mg gentamicin/day. The incidence of secondary achieved pneumonia was reduced from 70% to 18%. The endotracheal colonization of pathogenic microorganisms reached 29.6% concerning bacterial microorganisms and 61% concerning fungi, 51.8% of all specimen were sterile. During 4 years of investigation there were found 19 secondary resistances of different bacteria, 12 persisted. Serum concentrations of gentamicin under endotracheal administration of 40 mg in 6-h-intervals didn't reach therapeutic values. In case of renal disorder the dose interval should be prolonged to twelve hours.

Adult↗

PubMed2001

Isolated airway exposure to toluene diisocyanate results in skin sensitization.

Toluene diisocyanate (TDI), a highly reactive industrial chemical is a leading cause of occupational asthma in westernized countries. It has also been reported to be a skin sensitizer in mice and guinea pigs although instances of skin sensitivity in humans are rare. It is uncertain if skin-contact is necessary to initiate the dermal sensitization. This study sought to determine if exclusive airway exposure to TDI could result in skin sensitivity. A group of guinea pigs was administered 50 microl of 0.6% TDI intratracheally (it.), another group received intranasal (in.) application of 0.6, 1.2, or 1.8% TDI. Eighty percent (4/5) of the it.-dosed animals, and 92% (11/12) of in.-dosed animals exhibited skin sensitivity. None of 14 control animals gave a positive reaction to patch challenge with TDI. These findings indicate that exclusive exposure of the airways to TDI can result in skin sensitivity and suggest that such events may be possible in TDI workers and should be considered in all workers exposed via the airways to chemical sensitizers.

Administration, Inhalation↗

PubMed1990

A new approach to suppress bucking before extubation--lidocaine through modified endotracheal tube.

The conventional endotracheal tube was modified with an epidural catheter adhered on the concave aspect of it. The opening of the catheter is at the proximal margin of the cuff. Local anesthetic can be injected into the trachea, then desensitize the tracheal mucosa nearby the cuff. Thirty-four female gynecological patients underwent abdominal total hysterectomy were studied and divided into three groups. In group 1, anesthesia was maintained without special management. In groups 2 and 3, 2 mL gentian violet stained 4% lidocaine solution was administered intratracheally by two different methods 60-120 minutes before the conclusion of the surgery. The peak cuff pressures generated by the awakening patients were 53.8 +/- 2.2 cm H2O (mean +/- SE) in group 1, 47.3 +/- 2.5 cmH2O (Group 2) and 36.4 +/- 1.6 cmH2O Group 3) respectively. Bucking before awakening was also evaluated clinically and showed 100%, 73% and 0% in each group. Intratracheal administration of lidocaine in dose of 2 mL 4% showed significant effect for the suppression of bucking during the recovery of general anesthesia in group 2 and 3 compared with the group 1. Lidocaine administered through the catheter of modified endotracheal tube also resulted in less increase in the peak cuff pressure and even no clinically observed bucking than direct administered through the endotracheal tube. Gag reflex was preserved in all patients and none had suffered from aspiration postoperatively.

Adult↗

PubMed2006

Oligomerization of CXCL10 is necessary for endothelial cell presentation and in vivo activity.

The chemokine IFN-gamma-inducible protein of 10 kDa (IP-10; CXCL10) plays an important role in the recruitment of activated T lymphocytes into sites of inflammation by interacting with the G protein-coupled receptor CXCR3. IP-10, like other chemokines, forms oligomers, the role of which has not yet been explored. In this study, we used a monomeric IP-10 mutant to elucidate the functional significance of oligomerization. Although monomeric IP-10 had reduced binding affinity for CXCR3 and heparin, it was able to induce in vitro chemotaxis of activated T cells with the same efficacy as wild-type IP-10. However, monomeric IP-10 was unable to induce recruitment of activated CD8+ T cells into the airways of mice after intratracheal instillation. Use of a different IP-10 mutant demonstrated that this inability was due to lack of oligomerization rather than reduced CXCR3 or heparin binding. Molecular imaging demonstrated that both wild-type and monomeric IP-10 were retained in the lung after intratracheal instillation. However, in vitro binding assays indicated that wild-type, but not monomeric, IP-10 was retained on endothelial cells and could induce transendothelial chemotaxis of activated T cells. We therefore propose that oligomerization of IP-10 is required for presentation on endothelial cells and subsequent transendothelial migration, an essential step for lymphocyte recruitment in vivo.

Animals↗

PubMed1992

Factors affecting the release rate of terbutaline from liposome formulations after intratracheal instillation in the guinea pig.

Maximum duration of bronchodilator efficacy in inhaled liposome-based formulations depends on optimizing the in vivo release rate of the encapsulated bronchodilator. We investigated the effect of several formulation variables on the pulmonary residence time of 3H-terbutaline sulfate liposomes administered intratracheally in guinea pigs, using an improved method enabling the measurement of pulmonary drug absorption for extended periods of time in conscious animals. Half-lives of liposome-encapsulated 3H-terbutaline disappearance from the lungs and airways after instillation ranged from 1.4 to 18 hr and were markedly affected by liposome size, cholesterol content, and phospholipid composition. This study demonstrates that liposomes can significantly prolong the residence time of bronchodilators in the lungs and that precise control over the pulmonary residence time of encapsulated bronchodilators can be achieved by controlling formulation variables.

Absorption↗

PubMed1989

[Statistical analysis of body and lung mass of animals subjected to a single experimental insufflation of soil dust and electro-energetic ashes].

The studies were performed on 44 white female Wistar rats which were intratracheally administered the suspension of the soil dust and the electro-energetic ashes. The electro-energetic ashes were collected from 6 different local heat and power generating plants while the soil dust from several random places of our country. The statistical analysis of the body and the lung mass of the animals subjected to the single dust and ash insufflation was performed. The applied variants proved the statistically significant differences between the body and the lung mass. The observed differences are connected with the kinds of dust and ash used in the experiment.

Animals↗

PubMed1985

Respiratory functional changes on intratracheal challenge of sensitized rats.

Inbred PVG/c rats were sensitized to DNP19-ovalbumin by intraperitoneal injection. Sensitized rats when challenged with antigen developed characteristic brief interruptions of expiratory flow ('expiratory notching'). The functional residual capacity fell in rats challenged with antigen or saline but the fall was greater in those sensitized rats challenged with antigen. No greater alterations in respiratory rate, minute volume, airways resistance or dynamic compliance occurred on antigen as compared with saline challenge of sensitized rats, suggesting that the expression of immediate respiratory hypersensitivity in the rat is different from the asthmatic response in humans. The expiratory notching was reduced if an additional airways resistance was added in series to the tracheostomy tube. This may be explained as a result of reduction in the dynamic compression which normally produced the expiratory notching.

Airway Resistance↗

PubMed1984

The influence of amosite asbestos exposure on lung permeability.

The effect of amosite asbestos on permeability of the blood/air barrier in the lung was studied using an acute animal model. The ultrastructural tracer selected for the study was horseradish peroxidase which was given intravenously in animals that had been exposed intratracheally to asbestos. The acute period of study was either 1/2, 1, 2, 3, or 4 hr, or 1-7 or 14 days postexposure. The barrier in the normal lung was at the level of the alveolar epithelial lining. Leakage of exudate and tracer occurred through the altered barriers following asbestos exposure and the extent of leakage related directly to the degree of alveolitis and the asbestos present in the area. A trend toward recovery of the barrier occurred with the reestablishment of a more normal-appearing epithelial lining during the second week postexposure.

Animals↗

PubMed2001

Role of LPS and receptor subtypes in the uptake of TNF by the murine lung.

Tumor necrosis factor alpha (TNF) is an important mediator in lung injury. The kinetics of TNF uptake by the lung are not completely understood. In this study, we evaluated the role that lipopolysaccharide (LPS) and the two types of TNF receptor (p55 and p75) play in the uptake of circulating murine TNF by the murine lung. TNF radioactively labeled with 125I (I-mTNF) was administered intravenously (2 x 10(6) cpm/mouse) to mice with both receptors (wild-type) or to mice missing one (p55-/- or p75-/-) or both (p55-/- and p75-/-) TNF receptors. Blood to lung non-reversible sequestration (Ki) and reversible uptake (Vi) were measured with multiple-time regression analysis. Uptake by lung of I-mTNF in wild-type mice had reversible and non-reversible components. This uptake was decreased by intratracheal, but not by intravenous, LPS, suggesting modulation by local, rather than systemic, inflammation. The p75-/- deficient mice retained the Ki (saturable, non-reversible) component of TNF uptake, whereas p55-/- deficient mice retained the Vi (saturable, reversible) component of TNF uptake. Both Ki and Vi components of TNF uptake were absent in the lungs of p55-/- p75-/- deficient mice. These studies show that local inflammation inhibits the uptake of circulating I-mTNF by lung and that uptake consists of two distinguishable compartments: reversible uptake mediated by the p75 receptor and non-reversible sequestration mediated by the p55 receptor.

Animals↗

PubMedDate not supplied

Intratracheal administration of microcystin-LR, and its distribution.

Microcystin-LR (MCLR) was injected into mice intratracheally, absorption from the lungs was easy and it was confirmed that both the cause of death and lethality dose level were the same as by intraperitoneal injection treatment. An immunostaining method revealed that there was a time lag of about 60 min before accumulation of MCLR, and that it caused bleeding in the liver. Clearance from internal organs took about 2 weeks; during the initial stage (the first 2 days), the small intestine, kidney, cecum and large intestine were already involved. However, even after 2 weeks, small amounts of MCLR were still present in epithelial cells in the gastrointestinal mucosa.

Absorption↗

PubMed2001

Early recruitment of neutrophils determines subsequent T1/T2 host responses in a murine model of Legionella pneumophila pneumonia.

The contribution of neutrophils to lethal sensitivity and cytokine balance governing T1 and T2 host responses was assessed in a murine model of Legionella pneumophila pneumonia. Neutrophil depletion by administration of granulocyte-specific mAb RB6-8C5 at 1 day before infection rendered mice approximately 100-fold more susceptible to lethal pneumonia induced by L. pneumophila. However, this treatment did not alter early bacterial clearance, despite a substantial decrease in neutrophil influx at this time point. Cytokine profiles in the lungs of control mice demonstrated strong T1 responses, characterized by an increase of IFN-gamma and IL-12. In contrast, neutrophil-depleted mice exhibited significantly lower levels of IFN-gamma and IL-12, and elevation of T2 cytokines, IL-4 and IL-10. Immunohistochemistry of bronchoalveolar lavage cells demonstrated the presence of IL-12 in neutrophils, but not alveolar macrophages. Moreover, IL-12 was detected in lavage cell lysates by ELISA, which was paralleled to neutrophil number. However, intratracheal administration of recombinant murine IL-12 did not restore resistance, whereas reconstitution of IFN-gamma drastically improved bacterial clearance and survival in neutrophil-depleted mice. Taken together, these data demonstrated that neutrophils play crucial roles in primary L. pneumophila infection, not via direct killing but more immunomodulatory effects. Our results suggest that the early recruitment of neutrophils may contribute to T1 polarization in a murine model of L. pneumophila pneumonia.

Animals↗