107. Kongreß der Deutschen Gesellschaft für Chirurgie Berlin, 17.–21. April 1990, 1990
Die bronchoalveolare Lavage ist heute als eine routinemasig anzuwendehde Methode zur Gewinnung ce... more Die bronchoalveolare Lavage ist heute als eine routinemasig anzuwendehde Methode zur Gewinnung cellularer oder humoraler Faktoren aus dem Bronchoalveolarraum etabliert (1). Zur Verlaufskontrolle ist es bei bestimmten experimentellen bzw. klinischen Untersuchungsprotokollen wunschenswert, die BAL wiederholt durchzufuhren. Aus mehreren Untersuchungen ist bekannt, das die BAL-Prozedur einen Einstrom neutrophiler Granulocyten in den Bronchoalveolarraum induziert (2, 3). Widerspruchlich diskutiert wird, ob dieser BAL-Effekt lokal begrenzt ist oder ob er auch andere, initial nicht lavagierte Lungenareale betrifft (4, 5). Von besonderer klinischer Relevanz ist die Frage, ob die uber einen langeren Zeitraum wiederholte Durchfiihrung der BAL zu Veranderungen bzw. Schaden bronchoalveolarer Strukturen fuhrt.
Abstract: Specific regions in the rat larynx exhibit cellular changes in response to inhaled xeno... more Abstract: Specific regions in the rat larynx exhibit cellular changes in response to inhaled xenobiotics. These regions include the base of the epiglottis, ventral pouch, and medial surfaces of the vocal processes of the arytenoid cartilages 1,2. In order to collect information on the usefulness of trimming techniques, the influence of different vehicles, the impact of different application routes in toxicity studies, and differences between induced vs. spontaneous lesions, the data obtained from a large number of inhalation and non-inhalation studies performed in Wistar RCCHan TM: Wist rats at Harlan Laboratories Ltd Switzerland, all evaluated or reviewed by the same pathologist, were compiled for a detailed review. The value of different trimming techniques was deemed to be greatest for transverse and sagittolongitudinal section techniques, as compared to horizontolongitudinally section techniques. The comparison of lesions encountered in control rats of inhalation studies treated...
Oxygen supply is the most important requirement of type II photodynamic reactions. Prerequisite i... more Oxygen supply is the most important requirement of type II photodynamic reactions. Prerequisite in photodynamic tumor therapy is an intact tumor blood flow during irradiation. Most photosensitizers destroy tumor vessels due to accumulation in endothelial cells. As a prerequisite to develop novel photosensitizing drugs an in-vivo test system is required to quantitatively assess for inertness of those sensitizers to the
Summary The changes in the rat kidney described here following prolonged experimental shock over ... more Summary The changes in the rat kidney described here following prolonged experimental shock over a period of 1 to 79 days demonstrate in an animal model the pathogenetic processes occurring in the shock kidney. Shock was induced in 130 Wistar rats by a single or several intravenous injections of Escherichia coli neurotoxin (up to 8 injections). The kidneys were examined with the light and electron microscopes. Changes in the kidneys depended on the duration of the shock as well as on the number of injections and were characterized by three morphological phases. Phase 1 (1 to 5 days post injectionem [p. i.] with one or two neurotoxin injections) is marked by extensive interstitial oedama. In Phase 2 (beginning on the 5th day p. i.) the first mononuclear cellular infiltrates are seen in the interstitial connective tissue within the oedematous regions and intensify with increasing numbers of toxin injections and continuing shock. The cellular infiltrates are recruited from migratory mononuclear blood cells as well as through local cell proliferation. In this phase an atrophy of renal tubules can be observed in areas with marked expansion of the interstice. In the beginning of Phase 3 (20 days p. i. and later) there is an increase of collagen fibrils and fibroblasts. After about 30 days p. i. extensive foci of fibrosis are visible in the interstitial tissue of the kidney. The causes of this intensive mesenchymal reaction in shock, also involving other organs such as liver, lung, gastrointestinal tract and adrenal glands, are discussed. Zusammenfassung Pathogenese der Nierenveranderung im experimentellen protrahierten Schock Die vorliegende Arbeit beschreibt die Veranderungen an der Niere und die dabei ablaufenden pathogenetischen Prozesse nach experimentellem protrahierten Schock der Ratte uber einen Zeitraum von 1 bis 79 Tagen. Bei 130 Wistar-Ratten erfolgte die Schockauslosung durch ein- und mehrmalige (max. 8) intravenose Injektionen des Neurotoxin von Escherichia coli-Bakterien des Serotypes O 139:K82 (B). Die licht- und elektronenmikroskopisch festgestellten Nierenveranderungen waren dabei sowohl von der Schockdauer als auch von der Anzahl der Injektionen abhangig und liesen sich in 3 Phasen einteilen. Die erste Phase (1 bis 5 Tage nach 1 oder 2 Neurotoxin-Injektionen) ist gekennzeichnet durch ausgedehnte interstitielle Odeme. In der zweiten Phase (ab dem 5. Tage p. i.) kommt es in den odematisierten Bezirken des Interstitiums zu ersten mononuklearen Zellinfiltrationen, die sich mit zunehmender Schockdauer und mehrmaliger Toxininjektion verstarken. Die interstitiellen Zellansammlungen sind neben einer lokalen Zellproliferation auf eine Emigration mononuklearer Zellen aus dem Blutstrom zuruckzufuhren. In dieser Phase sind in den Bereichen mit deutlich verbreitertem Interstitium Anzeichen einer Atrophie der Nierentubuli zu beobachten. In der dritten Phase (20 Tage p. i. und spater) kann zunachst eine Vermehrung von Kollagenfibrillen und Fibroblasten festgestellt werden. Nach etwa 30 Tagen treten herdformig ausgedehnte Fibrosen im Interstitium der Nieren auf. Die Grunde dieser mesenchymalen Reaktion nach Schock, die auch andere Organe wie Leber, Lunge, Magen-Darmtrakt und Nebenniere erfast, werden diskutiert. Resume Pathogenese des modifications renales dans un choc experimental prolonge Ce travail decrit les modifications renales et les processus pathogenetiques en decoulant apres un choc experimental prolonge chez des rats pendant une periode de 1 a 79 jours. Chez 130 rats Wistar, le declenchement du choc a ete provoque par une ou plusieurs (maximum 8) injections intraveineuses de neurotoxine d'E. coli du serotype O 139:K82 (B). Les lesions renales etablies au microscope optique et electronique dependaient aussi bien de la duree du choc que du nombre des injections et ont ete divisees en 3 phases. La premiere phase (1 a 5 jours apres 1 ou 2 injections de neurotoxine) se reconnait a un oedeme interstitiel etendu. Dans la deuxieme phase (des le 5e jour p. i.), on constate les premieres infiltrations de cellules mononucleees dans l'interstitium cellulaire locale, a une emigration de cellules mononucleees a partir de la circulation sanguine. Dans les regions d'un interstitium nettement elargi, on observe dans cette phase une atrophie des tubuli renaux. Dans la troisieme phase (20 jours p.i. et plus tard), on a etabli tout d'abord une multiplication des fibrilles collagenes et des fibroblastes. Des fibroses etendues en foyers sont apparues dans l'interstitium des reins apres environ 30 jours. On discute les bases de cette reaction mesenchymateuse apres un choc qui atteint egalement d'autres organes tels le foie, les poumons, le tube gastro-intestinal et les surrenales. Resumen La patogenia de las modificaciones renales en el choque experimental prolongado Describe el trabajo presente las modificaciones habidas en el rinon y los procesos patogenicos que discurren con ello tras el choque experimental prolongado…
Previous repeated inhalation exposure studies revealed two independent organotropic effects of in... more Previous repeated inhalation exposure studies revealed two independent organotropic effects of inhaled propineb dust: One was restricted to the lung, the other to muscle weakness of hindlimbs. These effects were believed to be causally related to the principle decomposition products of this type of dithiocarbamate in the biological milieu and related to zinc and carbon disulfide. Two mechanistic 1-wk inhalation studies were performed, each focusing on one of these findings. The 7 x 6-h/day repeated-exposure inhalation study analyzed whether the nature of the response occurring at the alveolar level is "adaptive" or "early adverse" and whether soluble zinc is the causative agent. Groups of 18 female rats were exposed nose-only to mean concentrations of 0, 1.1, 5.5, and 25.8 mg propineb/m(3) and 6.9 mg ZnO/m(3). On postexposure days 1, 3, and 15 the time course of responses was analyzed by bronchoalveolar lavage (BAL), including quantification of Zn and metallothionein (MT) in BAL cells. Clinical evidence of muscular weakness was investigated separately in 20 female Wistar rats exposed to 70 mg propineb/m(3) on 5 consecutive days (6 h/day), followed by a 2-wk postexposure period. Clinical signs, body weights, and feed and water consumption were recorded as frequently as technically feasible. Fifty percent of rats received an oral cysteine supplementation to verify/refute the hypothesis that the incapacitation observed in previous studies is the cause of emaciation and associated impairment of CS(2) detoxification. The findings of the first study are consistent with this hypothesis, namely, that soluble Zn triggers a series of pulmonary events that is consistent with the homeostasis of this essential metal. It is concluded, accordingly, that the adjusted maximal workplace level for ZnO is also valid for propineb to preclude Zn-mediated responses to occur in the lung. With respect to muscular effects, this mechanistic study demonstrates further that the increased detoxification capacity afforded by oral supplementation of cysteine mitigates markedly the toxic potency of propineb. Procedural variables specific to the inhalation bioassay appear to be decisive for the elicitation of muscular effects. The major variable is considered to be the large drop in body weights associated with each exposure session and the concomitantly decreased uptake of essential nutritional factors (e.g., cysteine) involved in the detoxification of this compound. Accordingly, the muscular deficits elicited by high concentrations of propineb are viewed to be secondary effects in an animal species likely to be more susceptible to this type of change than humans (Pauluhn & Rosenbruch, 2003).
This article addresses results from repeated 1- and 4-wk inhalation exposure studies in Wistar ra... more This article addresses results from repeated 1- and 4-wk inhalation exposure studies in Wistar rats with solid aerosol (dust) atmospheres of propineb, a zinc bisdithiocarbamate homopolymer that is used as an agrochemical fungicide. Groups of 10 rats/sex were exposed nose-only to mean concentrations of 3.97, 11.24, and 21.95 mg propineb/m(3) using an exposure regimen of 6 h/day, 5 days/wk for 4 wk. Concentrations were selected based on results from a pilot study in which rats were exposed under identical conditions on 5 consecutive days for 6 h/day to mean concentrations of 10.1, 19.9, 38.1, and 78.7 mg/m(3). Both studies demonstrated that with respect to muscular effects female rats were remarkably more susceptible as compared to males. Female rats exposed to 11.24 mg/m(3) and above displayed characteristic signs of toxicity that included weakness and flaccid paralysis of hindlegs and ensuing immobilization that was considered to be the cause of emaciation and ensuing mortality in some rats. There was an apparent reciprocal relationship of concentration and the manifestation of clinical evidence of muscular dysfunction; that is, the onset in female rats exposed to 11.24, 21.95, 38.1, and 78.7 mg/m(3) was on days 15, 8, 4, and 3, respectively. In contrast, none of the male rats elaborated comparable effects up to 38.1 mg/m(3). Neuromuscular measures included leg grip strength and supplemented the clinical findings, whereas the landing foot splay was only minimally affected. Hematology and clinical pathology endpoints, including those addressing thyroidal function, were unobtrusive up to and including 78.7 mg/m(3). Lung weights were significantly increased in groups exposed to 21.95 mg/m(3) and above, especially in male rats. The microscopic examinations made in the 4-wk study demonstrated an increased incidence of intraalveolar material and enlarged, foamy alveolar macrophages at 3.97 mg/m(3) and above. Especially in female rats an atrophy of thigh muscle fibers, including increased nuclei and focal degeneration, occurred at 11.24 mg/m(3) and above. TTCA (2-thiazolidinethione-4-carboxylic acid) in urine, a metabolite and biomarker of exposure to CS(2), which is a putative breakdown product of propineb, was proportionally higher in the female rats exposed to 11.24 mg/m(3) and above. This biomarker appears to accumulate with time. This finding provides indirect evidence that the etiopathologic cause of neuromuscular changes is related to intermediary levels of CS(2). The data of this investigation suggest that the toxicity of inhaled propineb is characterized by two independent effects, namely, responses occurring at the alveolar level and muscular weakness, especially in female rats. With respect to the latter finding, the no-observed-adverse-effect level (NOAEL) of the 4-wk study is 3.97 mg/m(3). Further study is needed to clarify whether the pulmonary response observed at this exposure level is consistent with an adaptive or an early adverse effect.
Microparticles (MP) and fibres can be inhaled and cause inflammatory lung diseases. So far MP and... more Microparticles (MP) and fibres can be inhaled and cause inflammatory lung diseases. So far MP and fibres have not observed directly in the lung of living animals. A direct visualisation of particles and fibres would be important to study interactions with local and immigration host cells. In this methodical report latex beads were used as model particles for, e.g. nanoparticles, dusts, pollen or bacteria and were investigated using intravital fluorescence microscopy. Intravital fluorescence microscopy of the lung periphery is challenging because of the constant movement of the lung tissue and the heart. Chest window techniques have been described for investigation of lung vessels. For investigation of MP in larger areas of the lung surface this study presents an open chest-technique. Fluorescent MP were instilled into the trachea and could be observed in the alveoli of the right lung. Abundant numbers of MP were found within alveolar macrophages indicating that they are actively engulfed. Using the same setup also fluorescence labelled bacteria and its phagocytosis could be observed as shown in preliminary experiments. In conclusion, we present a method to analyse MP/fibres and its interaction with local and immigrating host cells in the living lung.
A study in young beagle dogs was performed in which the animals were treated for 2 weeks with cip... more A study in young beagle dogs was performed in which the animals were treated for 2 weeks with ciprofloxacin at oral doses of 0, 10, 30 or 90 mg/kg per day. Immediately after treatment half of the number of animals were killed and all weight-bearing joints were subject to a thorough gross and histopathological investigation, including special staining of the cartilage matrix, and immunohistochemistry as well as electron microscopy. The remaining animals were maintained for an additional 5-months treatment-free period before being killed. Again, all weight-bearing joints were subject to a thorough gross and histopathological investigation. After 14 days of treatment with ciprofloxacin, oral doses of 30 and 90 mg/kg induced the characteristic arthropathy (blisters, erosions) in juvenile beagle dogs. As expected the lesions persisted while the animals were growing. In contrast, and to our knowledge demonstrated for the first time, an oral dose of 10 mg/kg ciprofloxacin did not induce joint lesions after short-term treatment in juvenile beagle dogs and was also not associated with arthrotoxicity when the dogs became older.
Past experimentation indicates that in protracted shock lasting from days to weeks, intravascular... more Past experimentation indicates that in protracted shock lasting from days to weeks, intravascular processes [19] recede and perivascular and interstitial reactions dominate. This was observed in various organs, for example, kidney [3, 11], lung [15, 23], and the central nervous system [7]. The intra- and extravascular processes are referred to as the “vascular syndrome” [22]. In this paper the perivascular reactions in experimental protracted shock are explained in their chronologic sequence.
107. Kongreß der Deutschen Gesellschaft für Chirurgie Berlin, 17.–21. April 1990, 1990
Die bronchoalveolare Lavage ist heute als eine routinemasig anzuwendehde Methode zur Gewinnung ce... more Die bronchoalveolare Lavage ist heute als eine routinemasig anzuwendehde Methode zur Gewinnung cellularer oder humoraler Faktoren aus dem Bronchoalveolarraum etabliert (1). Zur Verlaufskontrolle ist es bei bestimmten experimentellen bzw. klinischen Untersuchungsprotokollen wunschenswert, die BAL wiederholt durchzufuhren. Aus mehreren Untersuchungen ist bekannt, das die BAL-Prozedur einen Einstrom neutrophiler Granulocyten in den Bronchoalveolarraum induziert (2, 3). Widerspruchlich diskutiert wird, ob dieser BAL-Effekt lokal begrenzt ist oder ob er auch andere, initial nicht lavagierte Lungenareale betrifft (4, 5). Von besonderer klinischer Relevanz ist die Frage, ob die uber einen langeren Zeitraum wiederholte Durchfiihrung der BAL zu Veranderungen bzw. Schaden bronchoalveolarer Strukturen fuhrt.
Abstract: Specific regions in the rat larynx exhibit cellular changes in response to inhaled xeno... more Abstract: Specific regions in the rat larynx exhibit cellular changes in response to inhaled xenobiotics. These regions include the base of the epiglottis, ventral pouch, and medial surfaces of the vocal processes of the arytenoid cartilages 1,2. In order to collect information on the usefulness of trimming techniques, the influence of different vehicles, the impact of different application routes in toxicity studies, and differences between induced vs. spontaneous lesions, the data obtained from a large number of inhalation and non-inhalation studies performed in Wistar RCCHan TM: Wist rats at Harlan Laboratories Ltd Switzerland, all evaluated or reviewed by the same pathologist, were compiled for a detailed review. The value of different trimming techniques was deemed to be greatest for transverse and sagittolongitudinal section techniques, as compared to horizontolongitudinally section techniques. The comparison of lesions encountered in control rats of inhalation studies treated...
Oxygen supply is the most important requirement of type II photodynamic reactions. Prerequisite i... more Oxygen supply is the most important requirement of type II photodynamic reactions. Prerequisite in photodynamic tumor therapy is an intact tumor blood flow during irradiation. Most photosensitizers destroy tumor vessels due to accumulation in endothelial cells. As a prerequisite to develop novel photosensitizing drugs an in-vivo test system is required to quantitatively assess for inertness of those sensitizers to the
Summary The changes in the rat kidney described here following prolonged experimental shock over ... more Summary The changes in the rat kidney described here following prolonged experimental shock over a period of 1 to 79 days demonstrate in an animal model the pathogenetic processes occurring in the shock kidney. Shock was induced in 130 Wistar rats by a single or several intravenous injections of Escherichia coli neurotoxin (up to 8 injections). The kidneys were examined with the light and electron microscopes. Changes in the kidneys depended on the duration of the shock as well as on the number of injections and were characterized by three morphological phases. Phase 1 (1 to 5 days post injectionem [p. i.] with one or two neurotoxin injections) is marked by extensive interstitial oedama. In Phase 2 (beginning on the 5th day p. i.) the first mononuclear cellular infiltrates are seen in the interstitial connective tissue within the oedematous regions and intensify with increasing numbers of toxin injections and continuing shock. The cellular infiltrates are recruited from migratory mononuclear blood cells as well as through local cell proliferation. In this phase an atrophy of renal tubules can be observed in areas with marked expansion of the interstice. In the beginning of Phase 3 (20 days p. i. and later) there is an increase of collagen fibrils and fibroblasts. After about 30 days p. i. extensive foci of fibrosis are visible in the interstitial tissue of the kidney. The causes of this intensive mesenchymal reaction in shock, also involving other organs such as liver, lung, gastrointestinal tract and adrenal glands, are discussed. Zusammenfassung Pathogenese der Nierenveranderung im experimentellen protrahierten Schock Die vorliegende Arbeit beschreibt die Veranderungen an der Niere und die dabei ablaufenden pathogenetischen Prozesse nach experimentellem protrahierten Schock der Ratte uber einen Zeitraum von 1 bis 79 Tagen. Bei 130 Wistar-Ratten erfolgte die Schockauslosung durch ein- und mehrmalige (max. 8) intravenose Injektionen des Neurotoxin von Escherichia coli-Bakterien des Serotypes O 139:K82 (B). Die licht- und elektronenmikroskopisch festgestellten Nierenveranderungen waren dabei sowohl von der Schockdauer als auch von der Anzahl der Injektionen abhangig und liesen sich in 3 Phasen einteilen. Die erste Phase (1 bis 5 Tage nach 1 oder 2 Neurotoxin-Injektionen) ist gekennzeichnet durch ausgedehnte interstitielle Odeme. In der zweiten Phase (ab dem 5. Tage p. i.) kommt es in den odematisierten Bezirken des Interstitiums zu ersten mononuklearen Zellinfiltrationen, die sich mit zunehmender Schockdauer und mehrmaliger Toxininjektion verstarken. Die interstitiellen Zellansammlungen sind neben einer lokalen Zellproliferation auf eine Emigration mononuklearer Zellen aus dem Blutstrom zuruckzufuhren. In dieser Phase sind in den Bereichen mit deutlich verbreitertem Interstitium Anzeichen einer Atrophie der Nierentubuli zu beobachten. In der dritten Phase (20 Tage p. i. und spater) kann zunachst eine Vermehrung von Kollagenfibrillen und Fibroblasten festgestellt werden. Nach etwa 30 Tagen treten herdformig ausgedehnte Fibrosen im Interstitium der Nieren auf. Die Grunde dieser mesenchymalen Reaktion nach Schock, die auch andere Organe wie Leber, Lunge, Magen-Darmtrakt und Nebenniere erfast, werden diskutiert. Resume Pathogenese des modifications renales dans un choc experimental prolonge Ce travail decrit les modifications renales et les processus pathogenetiques en decoulant apres un choc experimental prolonge chez des rats pendant une periode de 1 a 79 jours. Chez 130 rats Wistar, le declenchement du choc a ete provoque par une ou plusieurs (maximum 8) injections intraveineuses de neurotoxine d'E. coli du serotype O 139:K82 (B). Les lesions renales etablies au microscope optique et electronique dependaient aussi bien de la duree du choc que du nombre des injections et ont ete divisees en 3 phases. La premiere phase (1 a 5 jours apres 1 ou 2 injections de neurotoxine) se reconnait a un oedeme interstitiel etendu. Dans la deuxieme phase (des le 5e jour p. i.), on constate les premieres infiltrations de cellules mononucleees dans l'interstitium cellulaire locale, a une emigration de cellules mononucleees a partir de la circulation sanguine. Dans les regions d'un interstitium nettement elargi, on observe dans cette phase une atrophie des tubuli renaux. Dans la troisieme phase (20 jours p.i. et plus tard), on a etabli tout d'abord une multiplication des fibrilles collagenes et des fibroblastes. Des fibroses etendues en foyers sont apparues dans l'interstitium des reins apres environ 30 jours. On discute les bases de cette reaction mesenchymateuse apres un choc qui atteint egalement d'autres organes tels le foie, les poumons, le tube gastro-intestinal et les surrenales. Resumen La patogenia de las modificaciones renales en el choque experimental prolongado Describe el trabajo presente las modificaciones habidas en el rinon y los procesos patogenicos que discurren con ello tras el choque experimental prolongado…
Previous repeated inhalation exposure studies revealed two independent organotropic effects of in... more Previous repeated inhalation exposure studies revealed two independent organotropic effects of inhaled propineb dust: One was restricted to the lung, the other to muscle weakness of hindlimbs. These effects were believed to be causally related to the principle decomposition products of this type of dithiocarbamate in the biological milieu and related to zinc and carbon disulfide. Two mechanistic 1-wk inhalation studies were performed, each focusing on one of these findings. The 7 x 6-h/day repeated-exposure inhalation study analyzed whether the nature of the response occurring at the alveolar level is "adaptive" or "early adverse" and whether soluble zinc is the causative agent. Groups of 18 female rats were exposed nose-only to mean concentrations of 0, 1.1, 5.5, and 25.8 mg propineb/m(3) and 6.9 mg ZnO/m(3). On postexposure days 1, 3, and 15 the time course of responses was analyzed by bronchoalveolar lavage (BAL), including quantification of Zn and metallothionein (MT) in BAL cells. Clinical evidence of muscular weakness was investigated separately in 20 female Wistar rats exposed to 70 mg propineb/m(3) on 5 consecutive days (6 h/day), followed by a 2-wk postexposure period. Clinical signs, body weights, and feed and water consumption were recorded as frequently as technically feasible. Fifty percent of rats received an oral cysteine supplementation to verify/refute the hypothesis that the incapacitation observed in previous studies is the cause of emaciation and associated impairment of CS(2) detoxification. The findings of the first study are consistent with this hypothesis, namely, that soluble Zn triggers a series of pulmonary events that is consistent with the homeostasis of this essential metal. It is concluded, accordingly, that the adjusted maximal workplace level for ZnO is also valid for propineb to preclude Zn-mediated responses to occur in the lung. With respect to muscular effects, this mechanistic study demonstrates further that the increased detoxification capacity afforded by oral supplementation of cysteine mitigates markedly the toxic potency of propineb. Procedural variables specific to the inhalation bioassay appear to be decisive for the elicitation of muscular effects. The major variable is considered to be the large drop in body weights associated with each exposure session and the concomitantly decreased uptake of essential nutritional factors (e.g., cysteine) involved in the detoxification of this compound. Accordingly, the muscular deficits elicited by high concentrations of propineb are viewed to be secondary effects in an animal species likely to be more susceptible to this type of change than humans (Pauluhn & Rosenbruch, 2003).
This article addresses results from repeated 1- and 4-wk inhalation exposure studies in Wistar ra... more This article addresses results from repeated 1- and 4-wk inhalation exposure studies in Wistar rats with solid aerosol (dust) atmospheres of propineb, a zinc bisdithiocarbamate homopolymer that is used as an agrochemical fungicide. Groups of 10 rats/sex were exposed nose-only to mean concentrations of 3.97, 11.24, and 21.95 mg propineb/m(3) using an exposure regimen of 6 h/day, 5 days/wk for 4 wk. Concentrations were selected based on results from a pilot study in which rats were exposed under identical conditions on 5 consecutive days for 6 h/day to mean concentrations of 10.1, 19.9, 38.1, and 78.7 mg/m(3). Both studies demonstrated that with respect to muscular effects female rats were remarkably more susceptible as compared to males. Female rats exposed to 11.24 mg/m(3) and above displayed characteristic signs of toxicity that included weakness and flaccid paralysis of hindlegs and ensuing immobilization that was considered to be the cause of emaciation and ensuing mortality in some rats. There was an apparent reciprocal relationship of concentration and the manifestation of clinical evidence of muscular dysfunction; that is, the onset in female rats exposed to 11.24, 21.95, 38.1, and 78.7 mg/m(3) was on days 15, 8, 4, and 3, respectively. In contrast, none of the male rats elaborated comparable effects up to 38.1 mg/m(3). Neuromuscular measures included leg grip strength and supplemented the clinical findings, whereas the landing foot splay was only minimally affected. Hematology and clinical pathology endpoints, including those addressing thyroidal function, were unobtrusive up to and including 78.7 mg/m(3). Lung weights were significantly increased in groups exposed to 21.95 mg/m(3) and above, especially in male rats. The microscopic examinations made in the 4-wk study demonstrated an increased incidence of intraalveolar material and enlarged, foamy alveolar macrophages at 3.97 mg/m(3) and above. Especially in female rats an atrophy of thigh muscle fibers, including increased nuclei and focal degeneration, occurred at 11.24 mg/m(3) and above. TTCA (2-thiazolidinethione-4-carboxylic acid) in urine, a metabolite and biomarker of exposure to CS(2), which is a putative breakdown product of propineb, was proportionally higher in the female rats exposed to 11.24 mg/m(3) and above. This biomarker appears to accumulate with time. This finding provides indirect evidence that the etiopathologic cause of neuromuscular changes is related to intermediary levels of CS(2). The data of this investigation suggest that the toxicity of inhaled propineb is characterized by two independent effects, namely, responses occurring at the alveolar level and muscular weakness, especially in female rats. With respect to the latter finding, the no-observed-adverse-effect level (NOAEL) of the 4-wk study is 3.97 mg/m(3). Further study is needed to clarify whether the pulmonary response observed at this exposure level is consistent with an adaptive or an early adverse effect.
Microparticles (MP) and fibres can be inhaled and cause inflammatory lung diseases. So far MP and... more Microparticles (MP) and fibres can be inhaled and cause inflammatory lung diseases. So far MP and fibres have not observed directly in the lung of living animals. A direct visualisation of particles and fibres would be important to study interactions with local and immigration host cells. In this methodical report latex beads were used as model particles for, e.g. nanoparticles, dusts, pollen or bacteria and were investigated using intravital fluorescence microscopy. Intravital fluorescence microscopy of the lung periphery is challenging because of the constant movement of the lung tissue and the heart. Chest window techniques have been described for investigation of lung vessels. For investigation of MP in larger areas of the lung surface this study presents an open chest-technique. Fluorescent MP were instilled into the trachea and could be observed in the alveoli of the right lung. Abundant numbers of MP were found within alveolar macrophages indicating that they are actively engulfed. Using the same setup also fluorescence labelled bacteria and its phagocytosis could be observed as shown in preliminary experiments. In conclusion, we present a method to analyse MP/fibres and its interaction with local and immigrating host cells in the living lung.
A study in young beagle dogs was performed in which the animals were treated for 2 weeks with cip... more A study in young beagle dogs was performed in which the animals were treated for 2 weeks with ciprofloxacin at oral doses of 0, 10, 30 or 90 mg/kg per day. Immediately after treatment half of the number of animals were killed and all weight-bearing joints were subject to a thorough gross and histopathological investigation, including special staining of the cartilage matrix, and immunohistochemistry as well as electron microscopy. The remaining animals were maintained for an additional 5-months treatment-free period before being killed. Again, all weight-bearing joints were subject to a thorough gross and histopathological investigation. After 14 days of treatment with ciprofloxacin, oral doses of 30 and 90 mg/kg induced the characteristic arthropathy (blisters, erosions) in juvenile beagle dogs. As expected the lesions persisted while the animals were growing. In contrast, and to our knowledge demonstrated for the first time, an oral dose of 10 mg/kg ciprofloxacin did not induce joint lesions after short-term treatment in juvenile beagle dogs and was also not associated with arthrotoxicity when the dogs became older.
Past experimentation indicates that in protracted shock lasting from days to weeks, intravascular... more Past experimentation indicates that in protracted shock lasting from days to weeks, intravascular processes [19] recede and perivascular and interstitial reactions dominate. This was observed in various organs, for example, kidney [3, 11], lung [15, 23], and the central nervous system [7]. The intra- and extravascular processes are referred to as the “vascular syndrome” [22]. In this paper the perivascular reactions in experimental protracted shock are explained in their chronologic sequence.
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