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1.  Toxicological investigations on silicon carbide. 2. In vitro cell tests and long term injection tests. 
Silicon carbide (SiC) dust and other dusts for comparison were injected intratracheally at a high dose (50 mg) into rats and the response of the lungs and the lymph nodes was studied after an appropriate experimental period. The indices studied were: histological changes in the lung and lymph nodes, organ weights, the formation of collagenous fibres, and the appearance of quartz typical areas. According to several epidemiological investigations and previous experimental animal studies, SiC produces silicogenic (fibrogenic) effects. No changes in the tissues studied in terms of damaging fibrogenic effects could be found after eight months (first series) and three and 12 months (second series). In particular, the histological findings and the absence of quartz typical areas as well as the quantitative determination of collagen fibres show that SiC had no harmful effects on tissues. Based on these results, the extent to which other exposures during the production of SiC can be responsible for the established radiological alterations is discussed. Without doubt the following may be confounders: SiC fibres, crystalline SiO2 (quartz, cristobalite, tridymite), and possibly gaslike emissions (SO2). From the hygienic medical point of view the workplaces during SiC manufacture should be examined carefully. The substance SiC dust as such can be considered as inert from the experimental results based on qualitative and extremely sensitive procedures. A revision of the present threshold value for SiC in ther German MAK list is called for.
PMCID: PMC1061313  PMID: 8398874
2.  The Toxicity of Precipitated Silica 
The proportion of respirable particles in dust clouds generated from three samples of precipitated silica has been shown to range between one-quarter and one-third by weight.
After a single intratracheal dose of the silicas to rats, chemical analysis shows a progressive disappearance of silica from the lungs, though it is still detectable after 12 months. Some silica appears in the liver and kidneys but in two of the three samples none remains after 12 months.
The nature and duration of the lung lesions produced in rats after a single intratracheal injection are described. A mild degree of fibrosis was observed which showed a steady regression with time and was to some extent influenced by the nature of the silica injected. The lesions showed little resemblance to those arising from quartz and were more akin to those produced by non-fibrogenic dusts.
Recommendations are made for the precautions to be taken during the industrial handling of these dusts.
PMCID: PMC1038244  PMID: 13875292
3.  Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo. 
Journal of Clinical Investigation  1994;93(3):1298-1306.
Keratinocyte growth factor (KGF) administered as a single intratracheal injection causes a prominent dose-dependent proliferation of type II alveolar epithelial cells in the lungs of adult rats. The increase in mitotically active alveolar cells histologically appears as a micropapillary epithelial cell hyperplasia after 2 d and peaks after 3 d in the form of monolayers of cuboidal epithelial cells lining alveolar septae. Proliferating cell nuclear antigen immunohistochemistry confirmed the profound proliferative response induced by KGF. The hyperplastic alveolar lining cells contain immunoreactive surfactant protein B and are ultrastructurally noted to contain lamellar inclusions characteristic of surfactant-producing type II pneumocytes. Mild focal bronchiolar epithelial hyperplasia is noted but is much less striking than the proliferation of type II pneumocytes. Large airways are unaffected by KGF. Daily intravenous injection of KGF is also able to cause pneumocyte proliferation. The normal adult rat lung constitutively expresses both KGF and KGF receptor mRNA, suggesting that endogenous KGF may be implicated in the paracrine regulation of the growth of pneumocytes. In conclusion, KGF rapidly and specifically induces proliferation and differentiation of type II pneumocytes in the normal adult lung.
PMCID: PMC294086  PMID: 8132770
4.  Use of immunoblotting to detect Aspergillus fumigatus antigen in sera and urines of rats with experimental invasive aspergillosis. 
Journal of Clinical Microbiology  1990;28(7):1575-1579.
Immunoblotting was used to detect Aspergillus fumigatus antigen in sera and urines of immunosuppressed rats experimentally infected with A. fumigatus. Organisms were administered by both intravenous and intratracheal injections. Intravenously infected rats developed disseminated aspergillosis, but intratracheally infected rats developed pulmonary disease only. Fungal cultures of blood and urine samples from infected rats were negative. In the urines of intravenously infected rats, antigen was detected 24 to 48 h after infection; in the urines of intratracheally infected animals, antigen was detected on days 4 to 5 after infection. Antigen in serum was detected later than antigen in urine was. Following sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting of serum and urine samples, the most strongly reacting antigenic materials were found in the 88-, 40-, 27-, and 20-kilodalton regions. These dominant antigens appeared to be the same as those of control antigens prepared from A. fumigatus grown in vitro. Rabbit antiserum to Aspergillus filtrate antigen was found to be more immunoreactive than antiserum to mycelial or conidial antigen. No mycelium-specific antigens were detected.
PMCID: PMC267991  PMID: 2199519
1. The intratracheal injection of egg albumin or pneumococcus protein induces an inflammatory reaction in the lungs of rabbits previously inoculated with the respective antigen. 2. A similar reaction occurs following intratracheal injection of pneumococcus protein into the lungs of rabbits previously inoculated with heat-killed suspensions of the bacteria. 3. This reaction appears to be related to the presence of circulating antibody and to have the nature of the Arthus reaction. 4. A study of the reaction of the lung of rabbits to infection caused by intravenous injections of Pneumococcus reveals that (a) reactions occur irregularly in the lung; (b) in the lungs in which reactions do occur, the histological changes are not different in normal rabbits and in rabbits made resistant by previous intravenous or intracutaneous injections of pneumococci. 5. Intratracheal injection of pneumococcus protein followed by intravenous injection of virulent pneumococci on the next day does not alter the course and character of the infection in resistant rabbits. 6. The experiments reported in this paper bring no evidences to support the view that the lesions in the lungs of rabbits following the intravenous injection of pneumococci are modified by any previous state of sensitivity.
PMCID: PMC2132136  PMID: 19870031
6.  Administration of Bleomycin via the Oropharyngeal Aspiration Route Leads to Sustained Lung Fibrosis in Mice and Rats as Quantified by UTE-MRI and Histology 
PLoS ONE  2013;8(5):e63432.
Pulmonary fibrosis can be experimentally induced in small rodents by bleomycin. The antibiotic is usually administered via the intratracheal or intranasal routes. In the present study, we investigated the oropharyngeal aspiration of bleomycin as an alternative route for the induction of lung fibrosis in rats and mice. The development of lung injury was followed in vivo by ultrashort echo time magnetic resonance imaging (UTE-MRI) and by post-mortem analyses (histology of collagen, hydroxyproline determination, and qRT-PCR). In C57BL/6 mice, oropharyngeal aspiration of bleomycin led to more prominent lung fibrosis as compared to intranasal administration. Consequently, the oropharyngeal aspiration route allowed a dose reduction of bleomycin and, therewith, a model refinement. Moreover, the distribution of collagen after oropharyngeal aspiration of bleomycin was more homogenous than after intranasal administration: for the oropharyngeal aspiration route, fibrotic areas appeared all over the lung lobes, while for the intranasal route fibrotic lesions appeared mainly around the largest superior airways. Thus, oropharyngeal aspiration of bleomycin induced morphological changes that were more comparable to the human disease than the intranasal administration route did. Oropharyngeal aspiration of bleomycin led to a homogeneous fibrotic injury also in rat lungs. The present data suggest oropharyngeal aspiration of bleomycin as a less invasive means to induce homogeneous and sustained fibrosis in the lungs of mice and rats.
PMCID: PMC3646779  PMID: 23667616
7.  Enhanced translocation of particles from lungs by jaggery. 
Environmental Health Perspectives  1994;102(Suppl 5):211-214.
Because industrial workers in dusty or smoky environments seemed to experience no discomfort if they consumed the sugar cane product jaggery, experimental studies were undertaken to observe the effects of jaggery on dust-exposed rats. Rats with and without a single intratracheal instillation of coal dust (50 mg/rat) were orally gavaged with jaggery (0.5 g/rat, 5 days/week for 90 days). The enhanced translocation of coal particles from lungs to tracheobronchial lymph nodes was observed in jaggery-treated rats. Moreover, the jaggery reduced the coal-induced histological lesions and hydroxyproline contents of lungs. The lesions induced in omental tissue and regional lymph nodes by a single intraperitoneal injection of 50 mg each of coal and silica dust were modified by jaggery (0.5 g/rat, 5 days/week for 30 days). These findings along with the preventive action of jaggery on smoke-induced lung lesions suggest the potential of jaggery as protective agent for workers in dusty and smoky environments.
PMCID: PMC1567304  PMID: 7882934
8.  Effect of toxic thioureas on resistance of rats to growth in the lungs of intravenously and intratracheally seeded tumour cells. 
British Journal of Cancer  1978;37(1):92-104.
Clonogenic growth (colony-forming efficiency, CFE) of i.v. injected allogeneic W256 tumour cells in the lungs was markedly enhanced by treatment of rats with alpha-naphthyl thiourea (ANTU) injected i.p. from 2 h before to 2 h after the tumour cells. ANTU specifically increases pulmonary vascular permeability in adult rats and causes acute pulmonary oedema and pleural effusion. Inhibition of drug toxicity to the lungs by tachyphylaxis, specific antimetabolites or iodides did not abolish the effect of ANTU on CFE. CFE was not increased when cells were seeded by i.v. injection the lungs affected by advanced pulmonary oedema at 6 to 24 h after treatment with drug. ANTU did not enhance growth of intratracheally injected cells. Although ANTU has no cytotoxic or immunosuppressive action, treatment of tumour-immunized rats with ANTU caused apparent "breakdown" of tumour immunity in 50% of rats, by causing growth of tumour colonies in the lungs. Possible mechanisms for the ANTU-induced decrease in innate resistance to growth of tumour in the lungs are discussed.
PMCID: PMC2009496  PMID: 619962
9.  Role of infective, immunological, and chronic irritative factors in the development of silicosis. 
The effect of infective, immunological, and irritative factors on the onset and development of silicosis after intratracheal inoculation with 50 mg of tridymite was investigated on 220 specific pathogen free (SPF) female Sprague-Dawley rats. Even after 12 months the rats, always kept in SPF conditions after intratracheal injection of the dust, showed mainly granulomas with little tendency to confluence or to fibrohyalinosis. Chronic infective stimulation was obtained by keeping groups of SPF animals injected with tridymite for three, six, or 12 months in a conventional animal house, where they were exposed to the endemic bacterial flora. In these animal silicosis developed much more rapidly and produced much more severe confluent lesions than in rats always kept in SPF conditions. Horseradish peroxidase and ferritin given by intratracheal injection and by inhalation were histochemically shown mainly in the dust granulomas but did not accelerate the development of silicosis. Exposure to ozone increased the prevalence of lung infections and thus enhanced the silicosis in conventionally kept animals, without modifying the evolution of silicosis in SPF animals. These experiments showed that the presence of bacterial flora, and particularly bronchopulmonary infections, accelerated the development of silicosis and led to the suggestion that individuals subject to frequent bronchopulmonary infections are unfit for occupations necessitating exposure to silica dust.
PMCID: PMC1009019  PMID: 7093151
10.  PET Imaging of Lung Inflammation with [18F]FEDAC, a Radioligand for Translocator Protein (18 kDa) 
PLoS ONE  2012;7(9):e45065.
The translocator protein (18 kDa) (TSPO) is highly expressed on the bronchial and bronchiole epithelium, submucosal glands in intrapulmonary bronchi, pneumocytes and alveolar macrophages in human lung. This study aimed to perform positron emission tomography (PET) imaging of lung inflammation with [18F]FEDAC, a specific TSPO radioligand, and to determine cellular sources enriching TSPO expression in the lung.
An acute lung injury model was prepared by intratracheal administration of lipopolysaccharide (LPS) to rat. Uptake of radioactivity in the rat lungs was measured with small-animal PET after injection of [18F]FEDAC. Presence of TSPO was examined in the lung tissue using Western blot and immunohistochemical assays.
The uptake of [18F]FEDAC increased in the lung with the progress of inflammation by treatment with LPS. Pretreatment with a TSPO-selective ligand PK11195 showed a significant decrease in the lung uptake of [18F]FEDAC due to competitive binding to TSPO. TSPO expression was elevated in the inflamed lung section and its level responded to the [18F]FEDAC uptake and severity of inflammation. Increase of TSPO expression was mainly found in the neutrophils and macrophages of inflamed lungs.
From this study we conclude that PET with [18F]FEDAC may be a useful tool for imaging TSPO expression and evaluating progress of lung inflammation. Study on human lung using [18F]FEDAC-PET is promising.
PMCID: PMC3440397  PMID: 22984611
11.  Effects of monoclonal anti-PcrV antibody on Pseudomonas aeruginosa-induced acute lung injury in a rat model 
The effects of the murine monoclonal anti-PcrV antibody Mab166 on acute lung injury induced by Pseudomonas aeruginosa were analyzed in a rat model.
Lung injury was induced by the instillation of P. aeruginosa strain PA103 directly into the left lungs of anesthetized rats. One hour after the bacterial instillation, rabbit polyclonal anti-PcrV IgG, murine monoclonal anti-PcrV IgG Mab166 or Mab166 Fab-fragments were administered intratracheally directly into the lungs. The degree of alveolar epithelial injury, amount of lung edema, decrease in oxygenation and extent of lung inflammation by histology were evaluated as independent parameters of acute lung injury.
These parameters improved in rats that had received intratracheal instillation of either rabbit polyclonal anti-PcrV IgG, murine monoclonal anti-PcrV IgG Mab166 or Mab166 Fab-fragments in comparison with the control group.
Mab166 and its Fab fragments have potential as adjuvant therapy for acute lung injury due to P. aeruginosa pneumonia.
PMCID: PMC194171  PMID: 12943554
12.  Rat Neutrophils Prevent the Development of Tuberculosis  
Infection and Immunity  2004;72(3):1804-1806.
To understand the role of neutrophils in the development of rat tuberculosis in vivo, we utilized lipopolysaccharide (LPS)-induced neutrophilia in the lungs. LPS (50 μg/ml) was administered intratracheally to male Fischer rats. Rats were then infected with Mycobacterium tuberculosis by an airborne route. Intratracheal injection of LPS significantly blocked the development of pulmonary granulomas and significantly reduced pulmonary CFU (P < 0.01). LPS treatment with amphotericin B (an LPS inhibitor) or neutralizing anti-rat neutrophil antibody reversed the development of pulmonary lesions. LPS-induced transient neutrophilia prevented early mycobacterial infection. The timing of LPS administration was important. When given intratracheally at least 10 days after aerial infection, LPS did not prevent development of tuberculosis. Neutrophils obtained by bronchoalveolar lavage killed M. tuberculosis cells. These results indicate clearly that neutrophils participate actively in defense against early-phase tuberculosis.
PMCID: PMC356015  PMID: 14977991
13.  Comparative role of complement in pneumococcal and staphylococcal pneumonia. 
Infection and Immunity  1982;37(3):1270-1277.
To evaluate the role of complement in pneumococcal and staphylococcal pneumonia, we decomplemented rats with cobra venom factor and inoculated them intratracheally with Staphylococcus aureus or type 25 pneumococci. S. aureus produced a patchy bronchopneumonia in normal Sprague-Dawley or Lewis rats, and decomplementation did not increase the severity of staphylococcal infection in either rat strain as judged by quantitative cultures of the lungs and blood at 6, 24, and 48 h after inoculation. In contrast, decomplementation markedly increased the severity of pneumonia caused by type 25 pneumococci in Sprague-Dawley and Lewis rats. In Sprague-Dawley rats, decomplementation significantly increased the number of bacteria in the lungs at 3, 6, and 24 h of infection. Bacteremia developed early in decomplemented Sprague-Dawley rats, but the higher pulmonary bacterial counts did not appear to be caused by bacteremic seeding of the lungs. Decomplemented Sprague-Dawley rats inoculated intravenously with pneumococci failed to develop the very high levels of bacteria in the lungs that were observed when the rats were inoculated intratracheally. Moreover, decomplemented Lewis rats inoculated intratracheally with pneumococci developed significantly increased numbers of pneumococci in the lungs early in infection (3 and 6 h) when they had no detectable bacteremia. These data indicate that in murine models complement plays a major protective role against type 25 pneumococci in the lung, whereas complement is not important to host defense in staphylococcal pneumonia.
PMCID: PMC347674  PMID: 6982230
14.  Intratracheal Injection into Rats of Size-graded Silica Particles 
An experiment is described in which suspensions of size-graded silica particles of less than 1 μ, 1 to 3 μ, and 2 to 5 μ nominal size ranges and of equal surface area (600 sq. cm./ml.) were injected intratracheally into rats. After four months the rats were killed and the lungs were examined histologically for the grade of fibrosis and chemically for the silica and collagen content.
The results were analysed statistically and it was found that, under the experimental conditions described, the degree of fibrosis produced by the two large size fractions was more than that produced by the under 1 μ particles and was apparently related to the quantity (by weight) of the silica injected or the size of the particles and not to the surface area.
PMCID: PMC1008352  PMID: 4285720
15.  Pharmacokinetics of Gentamicin Administered Intratracheally to Rats 
The pharmacokinetics of intratracheally instilled and intravenously injected gentamicin were compared in the rat and analyzed by a one-compartment open model. The maximum concentration of gentamicin in plasma occurred within 10 min after intratracheal instillation. Considerable amounts of gentamicin were absorbed from lungs after intratracheal instillation, as shown by its concentrations in plasma and elimination in urine. The data suggest that the absorption of gentamicin from the pulmonary system would be sufficient to maintain therapeutic levels of this agent in plasma.
PMCID: PMC352427  PMID: 697344
16.  The antigen-presenting activities of Ia+ dendritic cells shift dynamically from lung to lymph node after an airway challenge with soluble antigen 
The Journal of Experimental Medicine  1995;181(4):1275-1283.
Dendritic cells (DC) are widely distributed in the lung where they are distinguished by their morphology and class II major histocompatibility complex (Ia) antigen expression. Although a role for DC as pulmonary antigen-presenting cell (APC) has been suggested, little is currently known concerning how these cells respond to inhaled antigens in vivo. Hen-egg lysozyme (HEL) was injected intratracheally into Lewis rats; DC were subsequently purified from the lung and regional lymph nodes (LN) at intervals of up to 14 d and examined for their ability to stimulate the proliferation of HEL-immune T cells in vitro in the absence of added HEL. Pulmonary DC displayed APC activities at 3 h and for up to 7 d after the injection of antigen. Dendritic cells in the draining hilar LN showed APC activities that appeared at 24 h, peaked at day 3, and then diminished progressively. After the primary sensitization, HEL- immune T cells were detected in hilar LN but not in the lung. A second airway challenge with HEL at day 14 yielded an antigen-specific pulmonary immune response, characterized histologically by the accumulation of mononuclear cells around lung venules. We conclude that APC activities shift from lung to lymph node during the response to inhaled antigen.
PMCID: PMC2191960  PMID: 7699319
17.  Long-Term (Postnatal Day 70) Outcome and Safety of Intratracheal Transplantation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Neonatal Hyperoxic Lung Injury 
Yonsei Medical Journal  2013;54(2):416-424.
This study was performed to evaluate the long-term effects and safety of intratracheal (IT) transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in neonatal hyperoxic lung injury at postnatal day (P)70 in a rat model.
Materials and Methods
Newborn Sprague Dawley rat pups were subjected to 14 days of hyperoxia (90% oxygen) within 10 hours after birth and allowed to recover at room air until sacrificed at P70. In the transplantation groups, hUCB-MSCs (5×105) were administered intratracheally at P5. At P70, various organs including the heart, lung, liver, and spleen were histologically examined, and the harvested lungs were assessed for morphometric analyses of alveolarization. ED-1, von Willebrand factor, and human-specific nuclear mitotic apparatus protein (NuMA) staining in the lungs and the hematologic profile of blood were evaluated.
Impaired alveolar and vascular growth, which evidenced by an increased mean linear intercept and decreased amount of von Willebrand factor, respectively, and the hyperoxia-induced inflammatory responses, as evidenced by inflammatory foci and ED-1 positive alveolar macrophages, were attenuated in the P70 rat lungs by IT transplantation of hUCB-MSCs. Although rare, donor cells with human specific NuMA staining were persistently present in the P70 rat lungs. There were no gross or microscopic abnormal findings in the heart, liver, or spleen, related to the MSCs transplantation.
The protective and beneficial effects of IT transplantation of hUCB-MSCs in neonatal hyperoxic lung injuries were sustained for a prolonged recovery period without any long-term adverse effects up to P70.
PMCID: PMC3575965  PMID: 23364976
Stem cells; cell transplantation; animal model; newborn; inflammation
18.  Evaluation of a new polyvalent Pseudomonas vaccine in respiratory infections. 
Infection and Immunity  1979;25(3):1029-1034.
A new polyvalent, cell wall extract, Pseudomonas aeruginosa vaccine (PEV-01), was evaluated by using a guinea pig model of experimental Pseudomonas pneumonia. Guinea pigs routinely developed fourfold rises in serum hemagglutinating Pseudomonas antibodies after four vaccine injections given over 2 weeks. Vaccinated animals survived an intratracheal Pseudomonas challenge (1 X 10(8) colony-forming units) significantly better (13 of 14 survived) than did a control group (5 of 14 survived) (P less than 0.01). Clearance of viable Pseudomonas from lung tissue was significantly better in vaccinees than controls at both 3 h (P less than 0.02) and 6 h (P less than 0.05) after infection. Both gross and histological examinations of lung tissue revealed less pulmonary tissue damage in vaccinated animals following Pseudomonas infection. Thus, PEV-01 Pseudomonas vaccine appears capable of eliciting a specific protective response in the guinea pig respiratory tract.
PMCID: PMC414551  PMID: 115786
19.  Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells attenuates Escherichia coli-induced acute lung injury in mice 
Respiratory Research  2011;12(1):108.
Human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuate hyperoxic neonatal lung injury primarily through anti-inflammatory effects. We hypothesized that intratracheal transplantation of human UCB-derived MSCs could attenuate Escherichia coli (E. coli)-induced acute lung injury (ALI) in mice by suppressing the inflammatory response.
Eight-week-old male ICR mice were randomized to control or ALI groups. ALI was induced by intratracheal E. coli instillation. Three-hours after E. coli instillation, MSCs, fibroblasts or phosphate-buffered saline were intratracheally administered randomly and survival was analyzed for 7 days post-injury. Lung histology including injury scores, myeloperoxidase (MPO) activity, and protein levels of interleukin (IL)-1α, IL-1β, IL-6, tumor necrosis factor (TNF)-α, and macrophage inflammatory protein (MIP)-2 as well as the wet-dry lung ratio and bacterial counts from blood and bronchoalveolar lavage (BAL) were evaluated at 1, 3, and 7 days post-injury. Levels of inflammatory cytokines in the lung were also profiled using protein macroarrays at day 3 post-injury which showed peak inflammation.
MSC transplantation increased survival and attenuated lung injuries in ALI mice, as evidenced by decreased injury scores on day 3 post-injury and reduced lung inflammation including increased MPO activity and protein levels of IL-1α, IL-1β, IL-6, TNF-α, and MIP-2 on day 3 and 7 post-injury. Inflammatory cytokine profiles in the lungs at day 3 post-injury were attenuated by MSC transplantation. MSCs also reduced the elevated lung water content at day 3 post-injury and bacterial counts in blood and BAL on day 7 post-injury.
Intratracheal transplantation of UCB-derived MSCs attenuates E. coli-induced ALI primarily by down-modulating the inflammatory process and enhancing bacterial clearance.
PMCID: PMC3166924  PMID: 21843339
Acute respiratory distress syndrome; Infection; Inflammation; Escherichia coli; Animal
20.  Preventive Effects of Pomegranate Seed Extract on Bleomycin-Induced Pulmonary Fibrosis in Rat 
Oxidative stress plays an important role in the pathogenesis of bleomycin-induced lung fibrosis and many antioxidant agents have been used for the treatment of this disease in animals.
To evaluate the antioxidant effects of pomegranate seed extract (PSE) on bleomycin treated rats.
Materials and Methods
Male Spraque – Dawley rats were divided into 5 groups: rats in groups I (bleomycin) and II (control) were given a single dose of bleomycin (7.5 IU/kg, intratracheally) in the bleomycin group and same amount of saline in the control, respectively. Treatment groups (III-V) were given PSE (100,200,400 mg/kg) orally a week before the bleomycin injection and this was continued for 3 weeks. At day 28, animals were sacrificed and lungs were removed for histological investigation.
Histological analysis showed that PSE could prevent pathological changes that were seen in the bleomycin group.
Results of the present study showed that hydroalcoholic extracts of pomegranate seeds had a significant protective effect against bleomycin-induced lung fibrosis by its antioxidant properties. The highest protective effect was observed for the 400 mg/kg dose.
PMCID: PMC3941905  PMID: 24624192
Pulmonary Fibrosis; Bleomycin; Antioxidants
21.  Protective immunization against chronic Pseudomonas aeruginosa pulmonary infection in rats. 
Infection and Immunity  1983;39(3):1377-1384.
Rats were immunized systemically with various doses of the polyvalent Pseudomonas aeruginosa vaccine PEV-01. After a series of two or three doses (25 to 50 micrograms each) at 8- to 11-day intervals, animals were challenged intratracheally by the agarose bead technique with a serotype 5 P. aeruginosa strain at periods of 9 to 42 days. Immunized animals developed circulating antibodies (primarily immunoglobulin M) against vaccine components at levels significantly higher than challenged, nonimmunized controls (P less than 0.005). Eight to ten days postinfection, histological sections of lungs from immunized animals showed only minimal inflammation associated with infectious foci (agarose beads) as compared with the extensive pathological changes of airways and parenchyma seen in infected nonimmunized control animals. However, no significant reduction in bacterial numbers was observed. Such protection lasted at least 6 weeks after the final immunization. It is speculated that the vaccine may contain components of cell surface proteins and virulence exoproducts.
PMCID: PMC348108  PMID: 6404823
22.  The aetiology of experimental fibrosing alveobronchiolitis induced in rats by paprika dust. 
The effect of a single intratracheal dose of respirable paprika (Hungarian) dust, paprika dust extract, and cellulose dust on the lungs of rats was examined sequentially one and three months after a treatment. Treatment with respirable paprika and cellulose dusts resulted in alveobronchiolitis at the end of the first month and fibrotic changes at the end of the third month. As the extract of paprika dust caused no histopathological alterations, it is assumed that the high cellulose content of paprika was responsible for the histological reactions.
PMCID: PMC1039271  PMID: 1637709
23.  Pulmonary toxicity of components of textile paint linked to the Ardystil syndrome: intratracheal administration in hamsters. 
OBJECTIVES: It was hypothesised from an epidemiological investigation that a formula change from Acramin FWR (a polyurea) to Acramin FWN (a polyamide-amine) had led to severe pulmonary disease in textile printing sprayers in SPAIN AND ALGERIA. To verify this, the pulmonary toxicity of the components of the paint systems involved was assessed in experimental animals. METHODS: Individual components and relevant mixtures, diluted in phosphate buttered saline, were given by intratracheal instillation of 2 ml/kg to hamsters. Pulmonary toxicity was assessed on days 3, 7, 14, 28, and 92 after a single intratracheal instillation, by histology and by measuring wet and dry lung weight, protein concentration, the activities of lactate dehydrogenase, alkaline phosphatase, beta-N-acetyl-glucosaminidase, and gamma-glutamyltransferase, inflammatory cell number and distribution in bronchoalveolar lavage fluid (BALF), and hydroxyproline content in dried lung tissue. RESULTS: Based on the doses that killed 50% of the animals (LD50s), the various components were found to be 10 to 1250 times more toxic when given intratracheally than when given orally (according to reported oral LD50s in rats). Acramin FWN, Acramin FWR, Acrafix FHN, or their mixtures caused lung damage. Protein concentration, enzyme activities, total cell number, and percentage of polymorphonuclear neutrophils were increased in BALF during the first week after intratracheal instillation. Lung weights remained high for at least a month. Histology showed inflammatory cell infiltration and subsequent fibrosis with collagen deposition. This finding was confirmed by an increased hydroxyproline content in dried lung tissue. Acramoll W did not show toxic effects. CONCLUSIONS: The study suggests that there is no major difference, in hamsters, between the acute intratracheal toxicity of Acramin FWR and that of Acramin FWN. Consequently, there is no simple toxicological explanation for the epidemiological hypothesis. However, the pulmonary toxicity of these non-irritant polymeric compounds is surprisingly high. The Ardystil disaster and these results should serve as a strong warning that conventional toxicity testing of chemicals does not necessarily protect workers against respiratory toxicity.
PMCID: PMC1128797  PMID: 9245943
24.  Lymphatic removal of fluids and particles in the mammalian lung. 
The structure and distribution of pulmonary lymphatics and their permeability to fluids and particulate materials have been investigated in the lungs of rats following fixation by combined intratracheal and vascular perfusion. In such preparations, the lymphatics remain in a distended state, and a close relationship to other structural components of the pulmonary interstitium is maintained. They were identified in regions with an abundant amount of connective tissue, forming an eleborate plexus within the pleura, the interlobular septum, peribronchial and perivascular areas. Recent data have shown that water-soluble molecules and particulate matter are removed from the interstitium along the lymphatic capillary (initial lymphatics) segment. It is distinguished by attenuated endothelial cells with extensively overlapping cell margins which are easily separated. We have studied this segment of the lymphatic vascular system following intratracheal injections of colloidal particles (ferritin and carbon) to determine the structural features responsible for the transport of large molecules and particulate materials across the lymphatic endothelial wall in the lung. The results showed that the tracer particles cross the lymphatic endothelial wall via the clefts of intercellular junctions. While the tracer particles were observed within vesicles, the question of transport across the lymphatic endothelium via plasmalemmal vesicles is still not settled since the number and size of vesicles containing tracer particles also increased with time. Intravascular injected dextran was also localized within the clefts of intercellular junctions and plasmalemmal vesicles. The results obtained with intratracheal and intravascular injected tracer substances are consistent with those observed in lymphatic capillaries for other tissues.
PMCID: PMC1568471  PMID: 6157524
25.  Vitamin A and the susceptibility of respiratory tract tissues to carcinogenic insult. 
The influence of vitamin A on the development of chemically induced lung carcinomas in rats was investigated. Rats were maintained on low, "normal" and excess levels of retinyl acetate (RA). Respiratory tract-squamous carcinomas were induced by intratracheal injections of 3-methylcholanthrene (3-MCA). The carcinogen doses used ranged from 1.25 to 10.0 mg of 3-MCA. Serial sacrifices conducted during the first 20 weeks following carcinogen exposure showed that metaplastic lung nodules, presumed to be precursors of later appearing carcinomas, occurred earlier and at higher incidence in rats maintained on low levels of RA than in rats maintained on moderate or high levels of RA. The development of invasive pulmonary carcinomas was enhanced at all four carcinogen doses in rats receiving low levels of RA as compared to rats receiving moderate or high levels of RA. No consistent difference in lung cancer incidence existed between the groups receiving normal and high levels of RA. The data clearly show an increased susceptibility of vitamin A-deficient rats to develop chemically induced lung cancers. Possible mechanisms underlying this effect are discussed.
PMCID: PMC1637367  PMID: 510247

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