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PubMed1996

Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality.

Keratinocyte growth factor (KGF) is a growth factor for type II pneumocytes. Type II pneumocyte hyperplasia, a common reaction to lung injury, has been postulated to play an important role in lung repair. The potential protective effect of KGF was therefore studied in rat models of radiation- and bleomycin-induced lung injury. Intratracheal instillation of KGF (5 mg/kg) 72 and 48 hours before 18 Gy of bilateral thoracic irradiation did not significantly improve survival, although histology showed less pneumonitis and fibrosis in KGF-pretreated as compared with control-irradiated rats. Intratracheal pretreatment with KGF in rats receiving intratracheal bleomycin (2.5 U) improved survival at 3 weeks to 100% (20/20 rats) from 40% (8/20 rats) in controls. All KGF-pretreated rats receiving bleomycin were well at 3 weeks and without histological evidence of pulmonary fibrosis whereas the 8 surviving control rats exhibited severe respiratory distress. Finally, in the most lethal challenge to the lung, rats pretreated with intratracheal KGF or saline were challenged with a combination of bleomycin (1.5 U) and bilateral thoracic irradiation (18 Gy). KGF-pretreated rats did not begin to die or show signs of respiratory distress until 7 weeks, whereas all saline-pretreated control rats receiving radiation and bleomycin died within approximately 4 weeks with severe respiratory distress and weight loss. In conclusion, radiation- and bleomycin-induced pulmonary injury and respiratory death are ameliorated by KGF pretreatment, suggesting a protective role for KGF-induced type II pneumocyte proliferation in lung injury.

Animals↗

PubMed1995

Interleukin-1 beta-induced neutrophil recruitment and acute lung injury in hamsters.

Administering recombinant interleukin-1 beta (IL-1 beta) intratracheally caused lung neutrophil accumulation and lung injury in hamsters. The percentage of leukocytes that were neutrophils increased progressively in lavages from lungs of hamsters given 25, 50, or 100 ng IL-1 beta intratracheally 2 h before. Lung injury, reflected by increased lung lavage protein concentrations and lung lavage hemoglobin concentrations, increased 2 h after administering 100 ng IL-1 beta. Lung injury, reflected by lung wet weight/body weight ratios, followed similar patterns, with significant increases occurring 2 h after insufflating 50 or 100 ng IL-1. Our results indicate that increased concentrations of IL-1 beta in lung airways can cause neutrophil recruitment and lung injury in hamsters. This mechanism may contribute to the development of lung neutrophil accumulation and lung injury that characterizes ARDS patients who have increased airway levels of IL-1 beta.

Acute Disease↗

PubMed1986

Lifetime effects of intratracheally instilled nickel subsulfide on B6C3F1 mice.

A nickel subsulfide (Ni3S2) lung tumor model for the study of metal carcinogenesis was evaluated using intratracheally dosed B6C3F1 mice. A preliminary study of the survival of mice 14 days after a single intratracheal dose of Ni3S2 displayed an LD50 of 4 mg/kg. A lifetime study was then initiated using five graded doses of Ni3S2 or saline alone, administered once a week for 4 weeks. Animals which survived more than 60 days after the final dose were evaluated by histopathology. The study was terminated 27 months after initiation when approximately 50% of the control animals had died. There was no increase in neoplastic or nonneoplastic lesions observed in animals treated with Ni3S2 nor was there evidence of damage to the organs of the respiratory tract from this treatment. The lack of significant biological response appears to be the result of relatively low tolerated dose, efficient lung clearance, and repair of early lung lesions.

Animals↗

PubMed1996

Pulmonary delivery of salmon calcitonin dry powders containing absorption enhancers in rats.

PURPOSE: To evaluate the effects of absorption enhancers in dry powders and in liquids, pulmonary absorption of salmon calcitonin (sCT) in various formulations was measured. METHODS: The dry powder of sCT was prepared by a freeze-drying method with a jet mill. After intratracheal administration of sCT dry powder and liquid (solution) preparations to rats, plasma sCT levels and calcium levels were measured. RESULTS: After intratracheal administration without absorption enhancers, sCT in the dry powder and in the liquid were absorbed nearly to the same degree. Absorption enhancers (oleic acid, lecithin, citric acid, taurocholic acid, dimethyl-beta-cyclodextrin, octyl-beta-D-glucoside) were much more effective in the dry powder than in the solution. The reason may be that the enhancers added to the dry powder dissolved at high concentrations in a trace volume of the fluid lining the alveolar epithelium. CONCLUSIONS: The present results suggest that the pulmonary absorption of peptides and proteins can be greatly improved by formulating them into dry powders with smaller amounts of enhancers than in liquid dosage forms.

Absorption↗

PubMed2003

Repression of bleomycin-induced pneumopathy by TNF.

Idiopathic pulmonary fibrosis is a chronic inflammatory lung disease with interstitial fibrosis. As a potent proinflammatory cytokine, TNF has been suggested to play critical roles in the pathogenesis of the human disease and its animal model, bleomycin-induced pneumopathy. However, studies using TNF-deficient mice have demonstrated that TNF also has an anti-inflammatory function. To determine the role of TNF in pulmonary inflammation induced by bleomycin, we injected bleomycin intratracheally into TNF-deficient mice. In this study, we demonstrated persistent and intense inflammation in TNF-deficient mice due to reduced apoptosis of inflammatory cells. We also showed that in TNF-deficient mice, challenge via airways with murine, but not human rTNF, efficiently eliminated inflammatory cells from the bronchoalveolar space by apoptosis, and thus promoted tissue repair of damaged lungs. Contrary to previous reports that showed that TNF was a central mediator of pulmonary inflammation, we have demonstrated that TNF is essential for repressing pulmonary inflammation in bleomycin-induced pneumopathy.

Administration, Inhalation↗

PubMed1976

[An animal experimental study on the retention rate of polycyclic aromatic hydrocarbons in the lung and in the subcutaneous tissue (author's transl)].

The retention rate of five polyaromatic hydrocarbons (PAH) (benzo(a)pyrene, dibenz(ah)anthracene, chrysene, pyrene, benz(a) anthracene) was studied after intratracheal instillation into syrian hamsters and subcutanous injection into mice. For subcutanous injection the PAH were solved in 0.5 ml tricaprylin, for intratracheal instillation a suspension in NaCl was used. The results were the following: 1. With respect to the retention rate of the five PAH the largest difference was found comparing the application modes. The ratio of the averaged half-time-values for the intratracheal test to the subcutanous test is about 1:35. 2. The retention rates for each polycyclic hydrocarbon differs significantly. An interrelation of PAH after application of a PAH-mixture was not detectable. 3. The retention rates determined in the lung and in the subcutanous tissue do not give a constant ratio concerning each PAH. Thus DBahA is retained in the lung as well as in the subcutanous tissue definitely longer than BaP. Chrysene and benz(a)anthracene behave - respecting the retention rate - in the subcutanous test like BaP. In lung tissue, however, the different behaviour becomes obvious: while benz(a)anthracene is eliminated most rapidly, chrysene can be detected for a relative long time.

Animals↗

PubMed1987

Lung fibrosis induced by diquat after intratracheal administration.

Diquat toxicity to lung was evaluated at various intervals after intratracheal administration to rats. Twelve hours after the injection, both type I and type II pneumocytes developed degenerative changes which were similar in nature to those induced by paraquat. A much larger dose of diquat, however, was needed for the changes compared to paraquat, which is known to be actively taken up by the lung. This morphological evidence suggests that diquat may cause alveolar damage by the same mechanism as paraquat, although it is not actively taken up by the lung. Moreover, initial alveolar damage induced by diquat was followed by lung fibrosis, as with paraquat. Since paraquat is a well known fibrogenic agent, the common property of these two agents in alveolar damage may be a key to interpreting the development of lung fibrosis.

Animals↗

PubMed1990

Activation of rat pulmonary lavage cells by intratracheal administration of polyinosinic-polycytidilic acid.

Systemic administration of biologic response modifiers (BRMs) is often limited by serious adverse effects. Local delivery of a BRM may provide a means to avoid systemic side effects while enhancing host defense. To test this hypothesis, the effects of intratracheal administration of the interferon inducer polyinosinic-polycytidilic acid (Poly-I:C) were examined. We demonstrated that intratracheal administration of Poly-I:C in rats results in alterations in pulmonary lavage cell number, population distribution, and function, suggestive of cellular activation. Following intratracheal instillation of 15, 75, or 150 mg of Poly-I:C, we observed a dose-dependent increase in Fc receptor-mediated phagocytosis, a dose-independent tumoricidal activity directed against xenogeneic P815 murine mastocytoma target cells, and a dose-independent decrease in superoxide anion (O2-) generation. With the exception of O2- generation, these functions returned to normal control levels by 7 days after a single dose of Poly-I:C. Thus, localized administration of Poly-I:C enhanced the host defense capability of pulmonary lavage cells, providing a rationale for compartmentalized immunoprophylaxis in the lung.

Analysis of Variance↗

PubMed1979

The fate of intratracheally instilled 3H-styrene oxide in the isolated perfused rat lungs.

The metabolism and covalent binding of intratracheally instilled 7-3H-styrene oxide in the isolated perfused lungs of control and cigarette smoke-exposed rats were investigated. After intratracheal instillation of 100 nmoles of 7-3H-styrene oxide the lungs were perfused for 16 min and the nonrecirculating perfusate was collected in two fractions: 0--8 min and 8--16 min. About 40 percent of the instilled dose was in the 0--8 min perfusion medium, mainly in the form of unmetabolized styrene oxide. However, the radioactivity in the 8--16 min perfusion medium and lung tissue itself was mainly in the form of water soluble metabolites, probably glutathione conjugates. The amount of styrene glycol was very small. Exposure of rat to cigarette smoke had no effect on the metabolism of styrene oxide or on the amount of covalent binding to the protein and nucleic acid fractions of the perfused lungs.

Animals↗

PubMed1985

Pathways of Cr (III) and Cr (VI) in the rat after intratracheal administration.

51Cr-labelled Cr3+ and CrO2-4 solutions were administered intratracheally to male rats in doses of 0.1 and 10 micrograms of Cr per rat to evidentiate metabolic differences especially in the lung and in the mechanisms of excretion. Twenty four hours after administration the highest 51Cr amount was present in the lungs for both valency states, being in the Cr (III)-treated group, however, about two times higher. In all other tissues tested the values in the Cr (VI)-treated animals were much higher. Intracellularly, in the Cr (III)-treated group more than 40% of the total lung homogenate was found in the nuclear fraction and only 10% in the cytosol. In the Cr (VI)-treated group 25% was present in the nuclei and more than 50% in the cytosol. Gel filtration 24 h after intratracheal injection showed that in both cytosols chromium was eluted in three peaks including a low-molecular-weight component. Quantitatively, however, the ratios between the 51Cr associated with the three peaks were significantly different between the Cr (III)- and the Cr (VI)-treated animals. This suggests that binding of chromium to low-molecular-weight components should be involved in the passage of this element from the lung to the other tissues. Excretion studies for 7 days showed that after this time the Cr (III)-treated animals excreted about 4% of the dose via urine and more than 36% via faeces, whereas in the Cr (VI)-treated rats the 51Cr was eliminated nearly equally between urine and faeces.

Animals↗

PubMed1979

Methods to evaluate the effects of toxic materials deposited in the lung on immunity in lung-associated lymph nodes.

Intratracheal instillation of sheep red blood cells (SRBC) induced a primary immune response in lung-associated lymph nodes of Chinese hamsters and Fischer-344 rats. Few or no anti-SRBC antibody forming cells (AFC) were found in the spleen or cervical lymph nodes after intratracheal immunization. The number of AFC was significantly suppressed in the lung-associated lymph nodes from hamsters exposed by inhalation of 239PuO2 and in rats exposed by intratracheal instillation of benzo(a)pyrene (BaP). Although the immunologic function of the lung-associated lymph nodes was suppressed by 239PuO2 and BaP exposure, there was no observable increase in the number of AFC in distant lymphoid tissues. These data indicate that damage to lung cells and/or cells in lung-associated lymph nodes can suppress immunity induced by deposition of antigen in the lung. Even though lung-associated lymph nodes in exposed animals contained lower numbers of AFC, antigen instilled into the lungs of exposed animals did not significatnly translocate to distant lymphoid tissues. This indicates that the antigen filtering capacity of the lung-associated lymph nodes was not altered.

Aerosols↗

PubMed1975

Effects of intratracheal instillation of dactinomycin on pulmonary edema and phosphatase activity of the lung lavage fluid in rats.

Intratracheal (i.t.) administration of protein synthesis inhibitors produced pulmonary edema. Of those inhibitors studied, dactinomycin (act. D) was the most potent. Severity of lung damage due to act. D was dose- and almost age-related. Maximal intensity of pulmonary edema was reached on the 3rd day following administration and remained constant for 14 days. Histopathological studies revealed confluent edema of the entire lung. Pretreatment with act D induced tolerance to an LD100 edematogenic dose of thiourea. The effects of i.t. instillation of act. D appear to be localized in the pulmonary tissue. Lung lavage fluid collected from drug-treated rats had higher acid and alkaline phosphatase activities, higher protein content and more leukocyte infiltration than that of control.

Animals↗

PubMed2006

Increased susceptibility of the lungs of hyperthyroid rats to oxidant injury: specificity of effects.

Results from previous studies indicate that hyperthyroidism increases the risk of ozone-induced lung toxicity. This observation raised the possibility that pulmonary damage from other oxidant substances might be greater in a hyperthyroid state. To address this hypothesis, pulmonary responses to crystalline silica, a particulate with oxidant properties, were evaluated in normal or hyperthyroid adult male rats. To induce a hyperthyroid condition, time-release pellets containing thyroxine were implanted subcutaneously; control rats received placebo pellets. After 7 days, the animals were exposed to saline or silica (0.1mg/100g BW or 1.0mg/100g BW) by intratracheal instillation. Following silica treatment, there was a dose-related increase in bronchoalveolar lavage (BAL) albumin levels and neutrophil numbers. However, the effects of silica were similar in both normal and hyperthyroid rats. These findings were confirmed and contrasted with those regarding ozone (1ppm, 4h inhalation) in a subsequent experiment. The results indicated that, although exposure to either ozone or silica resulted in increases in BAL albumin levels and neutrophil numbers, only responses to ozone were enhanced in hyperthyroid rats. These findings suggest that specificity exists in regards to the modulation of oxidant-induced lung damage and inflammation by thyroid hormones.

Albumins↗

PubMed2001

Differential regulation of airway mucin gene expression and mucin secretion by extracellular nucleotide triphosphates.

The effects of extracellular nucleotide triphosphates on the stimulation of mucin production by airway epithelial cells were examined. The order of potency in stimulating mucin secretion in primary cultures of human tracheobronchial epithelial cells is: uridine 5'-triphosphate (UTP) approximately equal to adenosine 5'-triphosphate (ATP) approximately equal to ATP-gamma-S > uridine 5'-diphosphate approximately equal to adenosine 5'-diphosphate > alpha,beta-methylene ATP >> adenosine. However, only UTP can increase mucin gene (MUC5AC, MUC5B) expression; ATP and other analogues have no stimulatory effect. The stimulation of MUC5AC and MUC5B expression by UTP is time- and dose-dependent. A similar effect on the elevation of mucous cell population in mouse airway epithelium can be demonstrated in vivo by an intratracheal instillation of UTP-saline solution. The stimulatory effect of UTP or ATP on mucin secretion was inhibited by pertussis toxin, U73122, and Calphostin C, but not by PD98059, suggesting a G-protein/ phospholipase (PL) C/protein kinase (PK) C-dependent and mitogen-activated protein kinase (MAPK)-independent signaling pathway. However, the stimulatory effect of UTP on mucin gene expression was sensitive to pertussis toxin and PD98059, but not to Calphostin C and U73122, suggesting a G-protein/MAPK-dependent and PLC/PKC-independent signaling pathway. These findings are the first demonstration that UTP, a pyrimidine nucleotide triphosphate, can enhance both mucin secretion and mucin gene expression through different signaling pathways.

Adenosine Triphosphate↗

PubMed1999

Short-term inflammatory responses following intratracheal instillation of fine and ultrafine carbon black in rats.

Ultrafine carbon black (ufCB) 14 nm in diameter and fine carbon black (CB) 260 nm in diameter were instilled intratracheally in rats at mass of 125 microg, and the bronchoalveolar lavage (BAL) profile at 6 h was assessed. UfCB generated a 50% neutrophil alveolitis 6 h after intratracheal instillation compared to CB, which showed similar activity to the phosphate-buffered saline (PBS) vehicle control. UfCB instillation also produced a marked increase in lactate dehydrogenase (LDH) levels in BAL fluid, which was associated with increased epithelial permeability measured as total protein. In contrast, CB had much less of an effect in increasing BAL protein. Although both particle types caused a decrease in glutathione (GSH) in lung tissue compared to control, the greatest depletion was seen in ufCB-treated animals. To investigate time response, bronchoalveolar lavage was carried out at 6 h, 24 h, and 7 days after a single 125-microg instillation of ufCB. Neutrophil influx was relatively persistent and was still maintained 7 days later. Tumor necrosis factor (TNF) production by BAL leukocytes increased gradually postinstillation, whereas NO production became significantly higher at 24 h after instillation and remained at raised levels up to 7 days. Higher doses of CB caused more inflammation than the ufCB. Thus, in the instillation model, a localized dose of particle over a certain level causes the particle mass to dominate the response, rather than the surface area. In contrast to the effect of CB, which showed a dose-related increasing inflammatory response, ufCB at the highest dose caused less of a neutrophil influx than at the lower dose. Six hours after intratracheal instillation, the threshold dose for neutrophil influx occurred at 50 microg. Calculation of surface area of particles instilled suggested that this was likely to be an overload-inducing dose of particles, as gauged from recent experiments with inhaled particles. In summary, this study provides evidence in a rat instillation model that ufCB has greater ability than CB to produce lung inflammation and oxidant stress at a relatively low dose of 125 microg. At high doses, however, BAL is not a reliable indicator of pulmonary response, since the overall response seems to scale to mass or volume of instilled particulate without an influence of surface area.

Animals↗

PubMed2006

Effects of diesel exhaust on lung inflammation related to bacterial endotoxin in mice.

We have previously shown that intratracheal instillation of diesel exhaust particles enhances lung inflammation and lung expression of proinflammatory cytokines and chemokines related to bacterial endotoxin (lipopolysaccharide) in mice. The present study was designed to elucidate the effects of inhalation of diesel exhaust on lung inflammation related to lipopolysaccharide. ICR mice were exposed for 12 hr to clean air or diesel exhaust at a soot concentration of 0.3, 1.0, or 3.0 mg/m(3) after intratracheal challenge with 125 microg/kg of lipopolysaccharide. Lung inflammation and lung expression of proinflammatory chemokines such as macrophage chemoattractant protein-1 and keratinocyte chemoattractant were evaluated 24 hr after intratracheal administration. Diesel exhaust inhalation decreased lipopolysaccharide-elicited inflammatory cell recruitment into the bronchoalveolar lavage fluid as compared with clean air inhalation. Histological study demonstrated that exposure to diesel exhaust did not affect lipopolysaccharide-enhanced neutrophil recruitment into the lung parenchyma. Lipopolysaccharide instillation elevated lung expression of macrophage chemoattractant protein-1 and keratinocyte chemoattractant under clean air or diesel exhaust inhalation. However, diesel exhaust exposure did not influence but rather did suppress these levels in the presence of lipopolysaccharide. These results suggest that short-term exposure to diesel exhaust did not exacerbate lung inflammation related to bacterial endotoxin.

Air Pollutants↗

PubMedDate not supplied

Pharmacokinetics of gentamicin administered intratracheally or as an inhalation aerosol to guinea pigs.

The pharmacokinetics of gentamicin were studied after intratracheal, inhalation, and iv administration to guinea pigs. Gentamicin injected intratracheally was almost completely systemically available. The comparison of the gentamicin plasma AUCs after inhalation and iv administration showed that an inhalation exposure lasting 10 min resulted in an absorption of 1.13 mg gentamicin/kg body weight into systemic circulation. This absorbed dose was 40.4 or 67.3% of the amount of gentamicin inhaled, depending on tidal volume assumed, and 1.4% of the amount of gentamicin aerosolized. The postinhalation gentamicin concentration in the lungs decreased with a half-life of 67.3 min. The data differentiate topical pulmonary gentamicin from systemic gentamicin and give a rational basis for study of the mechanism of the therapeutic effect of gentamicin inhalation aerosol in bronchopulmonary infections.

Aerosols↗

PubMed1993

Monitoring of total chromium in rat fluids and lymphocytes following intratracheal administration of soluble trivalent or hexavalent chromium compounds.

1. Intratracheal instillation of sodium dichromate (CrVI) and chromium acetate hydroxide (CrIII) to male Wistar rats gave rise to increased chromium concentrations in whole blood, plasma and urine up to 72 h post exposure; peak concentrations were reached at 6 h after exposure. 2. The ratio of whole blood chromium to plasma chromium concentrations was significantly different for Cr(VI) and Cr(III) treatments. Both blood chromium and plasma chromium assays should therefore be used for the assessment of chromium exposure. 3. Chromium was also detected in peripheral lymphocytes. Cr(VI), but not Cr(III) accumulated significantly in the lymphocytes after treatment. These cells have potential to be used for biomarkers of the assessment of exposure to chromium compounds.

Acetates↗