Typical Inflammatory Response Research Articles

The effects of carmeda bioactive surface on human blood components during simulated extracorporeal circulation

Postoperative morbidity after cardiopulmonary bypass most commonly manifests as bleeding diatheses or pulmonary dysfunction. The pathophysiology has been attributed to the activation of cellular and humoral components of blood after contact with an artificial surface. Development of a surface that would be nonthrombogenic and also would constitute a less potent inflammatory stimulus would therefore be beneficial. In the following experiments, we evaluated the heparin-bonded Carmeda Bioactive Surface (Medtronics Cardiopulmonary, Anaheim, Calif.) in an in vitro model of extracorporeal circulation at standard-dose heparin (5 U/ml), to examine the effects of the surface treatment on activation of blood elements, and at reduced-dose heparin (1 U/ml), to determine whether surface-bound heparin would serve as an effective anticoagulant. During the initial recirculation period, platelet counts in the Carmeda ( n = 12) circuits were preserved at both doses of heparin and compared with control values ( n = 12): At 5 U/ml, control 36% ± 4% (mean ± standard error of the mean) versus Carmeda 81% ± 5%; at 1 U/ml, 43% ± 3% versus 61% ± 10%, expressed as a percent of baseline at 30 minutes, p < 0.05. Furthermore, plasma levels of platelet factor 4 and β-thromboglobulin were significantly reduced in the Carmeda circuits throughout the experiment: At heparin 5 U/ml, 2500 ± 340 ng/ml versus 604 ± 191 ng/ml; at 1 U/ml, 2933 ± 275 ng/ml versus 577 ± 164 ng/ml of platelet factor 4 at 2 hours ( p < 0.05). The pattern of β-thromboglobulin release was similar, with effects more pronounced at the lower dose of heparin. Surface modification also reduced leukocyte depletion ( p < 0.05) and release of elastase at both concentrations of heparin (5 U/ml, 0.72 ± 0.29 ng/ml versus 0.33 ± 0.23 ng/ml; 1 U/ml, 0.85 ± 0.08 ng/ml versus 0.20 ± 0.05 ng/ml, at 2 hours, p < 0.05). Moreover, as heparin concentration was reduced, Carmeda surface treatment significantly decreased generation of C3a des Arg (1 U/ml, 14,410 ± 3558 ng/ml versus 3053 ± 1039 ng/ml at 2 hours, p < 0.05). Although heparin bonding was originally intended to obviate the need for systemic heparinization, Carmeda treatment did not reduce fibrinopeptide A generation at the lower dose of heparin. In summary, Carmeda treatment failed to exhibit anticoagulant efficacy in this model; however, the data suggest that surface modification may have a role in ameliorating the typical inflammatory response initiated by blood contact with an artificial surface. (J T HORAC C ARDIOVASC S URG 1996;111:1073-84)

Successful 48-h liver preservation by controlling nutritional status of donor and recipient.

The nutritional status of the donor has been shown to affect the outcome of liver transplantation in the rat. It has been proposed that this may be due to inhibition of Kupffer cell induced injury to the reperfused organ, which leads to an inflammatory type response. In this study we investigated how altering the nutritional status of the recipient affects the outcome of liver transplantation after preservation of the liver for 44 or 48 h in the University of Wisconsin (UW) solution. The nutritional status of the rats was altered by either fasting or by feeding an essential fatty acid free diet (EFAD) for 2 months. This type of diet has been shown to reduce significantly the inflammatory response in rats. Survival after 44-h preservation of livers from fed donors (fed a standard laboratory diet) transplanted to fed recipients was 29% (2/7) but increased to 80% (4/5) when the recipient was fed the EFAD diet. After 48-h preservation, there were no survivors under either of these two dietary combinations. However, survival was 100% after 48-h preservation if the donor had been fasted for 4 days and the recipient was fed the EFAD. These results showed that the nutritional status of the donor and recipient are important factors in the outcome of liver transplantation. How nutritional factors affect liver preservation and transplantation are not clear but may be related to the inflammatory response regulated by Kupffer cells and circulating neutrophils in the liver, both of which are influenced by the diet of the animal.

Induction of rat alpha-1-acid glycoprotein by phenobarbital is independent of a general acute-phase response

Phenobarbital (PB) induces transcription of the α1-acid glycoprotein (AGP) gene, one of the major positive acute-phase proteins, the expression of which is controlled by a specific combination of glucocorticoids and cytokines. This raises questions as to the involvement of glucocorticoids and cytokine pathways in the PB-mediated effect on AGP gene expression. We found that the pattern of whole-serum proteins in PB-treated rats differed markedly from that observed during a typical acute inflammatory response (in turpentine-treated rats): levels of some positive acute-phase proteins (APP) increased slightly (α1-acid glycoprotein, haptoglobin, hemopexin and T-kininogen), while levels of α2 macroglobulin, the most sensitive marker of the acute-phase reaction, decreased. Among the negative APP, neither albumin nor prealbumin decreased while CBG increased. The cytokines involved in AGP gene regulation (mainly IL1, IL6 and TNFα) do not therefore seem to mediate the effect of PB on acute-phase protein expression. Glucocorticoid involvement is also ruled out by the observed enhancement of the effect of PB on AGP expression in adrenalectomized animals. Our results suggest that phenobarbital acts on AGP expression by a mechanism independent of the inflammatory pathway.

Pregnancy maintenance and parturition: the role of prostaglandin in manipulating the immune and inflammatory response.

PREGNANCY represents a delicate balance between the requirements of the growing fetus and the maternal immune system that could potentially reject the semi-allogeneic fetal ‘graft’ (1). This balance requires an immune tolerance of the fetal tissue and a local suppression of an inflammatory response, but at the time of parturition a selective use of the inflammatory response could provide an effective mechanism for delivering the baby (2). The inflammatory response can be regarded as the effector arm of the immune system, which can be activated independently. In nonreproductive tissue, glucocorticoids afford control. However, during pregnancy and particularly in the uterus, it is likely that progesterone with its immunosuppressive and anti-inflammatory properties (3) contributes to the regulation of inflammatory-type responses. The prominent role of progesterone in maintaining pregnancy is demonstrated by the action of antiprogesterone steroids such as RU486 (Mifepristone) that can disrupt pregnancy at any...

Human chorionic gonadotropin induces interleukin-1 gene expression in rat Ley dig cells in vivo

Luteinizing hormone (LH)/human chorionic gonadotropin (hCG) causes inflammatory-type responses in the testis. In the present study, we evaluated the effects of hCG on Leydig cell interleukin-1 (IL-1) gene expression. Using monoclonal antibody (ED2) staining for macrophages, our Leydig cell preparations had no significant contamination with macrophages. When purified Leydig cells from normal rats were cultured for 24 h and then treated with IL-1β (1–100 ng/ml) for 6 h, IL-1β induced dose-dependent increases in IL-1β mRNA levels. IL-1β also induced IL-lα mRNA accumulation; however, the level of IL-1α mRNA was much lower than that of IL-1β mRNA. When rats were treated with either saline or hCG (5 units i.p.), hCG markedly induced IL-1β mRNA accumulation in purified Leydig cells at 6 h which persisted for over 24 h. However, hCG had no direct effect on purified Leydig cell or crude interstitial cell IL-1 mRNA levels. Our results suggest that inflammatory effects of hCG in vivo may be mediated by increased IL-1 gene expression in Leydig cells.

Histopathological progression of hemic neoplasms in the tropical crab Paratelphusa hydrodromous (Herbst) treated with sublethal cadmium chloride

Tropical crab Paratelphusa hydrodromous were exposed in the laboratory to five sublethal cadmium chloride concentrations (0.02, 0.05, 0.25 and 0.50μM/L) for 30 days to evaluate the cellular inflammatory and chronic pathologic responses. The most frequent pathologic responses of hepatopancreas exposed to 0.25–0.50 μM CdCl2/L were atrophy of R-cells and the development of granulomatous reaction consisting of granulocytes and monomorphic basophilic cells. Coagulative necrosis was evident in the young oocytes at 0.05 μM CdCl2/L which was accompanied by the increased vitellophagia of follicle cells. Thirty-day exposure to 0.25–0.50 μM CdCl2/L shortened the reproductive life span of the crabs by inducing spontaneous atresia and granulocytosis. Eosinophilic granulocytes, the most numerous cell type found in the necrotic centers, phagocytosed the masses of cellular debris and yolk from cadmium-induced atretic oocytes. The widespread proliferation of basophilic cells related to hyalinocyte with high nucleocytoplasmic ratio would suggest the development of hemic neoplasia. Heavy granulocytic infiltration was the typical cellular inflammatory response during chronic pathological conditions.

Acute Inflammatory Response to Sheep Red Blood Cell Challenge in Mice Treated with 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD): Phenotypic and Functional Analysis of Peritoneal Exudate Cells

TCDD is a widespread environmental contaminant of concern to human health because of its well-recognized immunotoxicity in laboratory animals. Suppression of the murine antibody response to xenogeneic erythrocytes has been shown to be one of the most sensitive assays for TCDD immunotoxicity. However, the cellular mechanisms underlying the suppressed immune function have not been fully elucidated. In the present studies, peritoneal macrophage recruitment, activation, and antigen-presenting function in response to sheep red blood cell (SRBC) injection were compared in C57B1/6 mice treated with a single oral dose of 0 or 5 μg TCDD/kg. In vehicle-treated mice, SRBC injection induced a typical inflammatory response in the peritoneal cavity. Within 6 hr, the number of neutrophils increased and remained elevated until 40 hr. Macrophage numbers increased at 24 hr and remained elevated through 72 hr. In TCDD-treated mice, a hyperinflammatory response to SRBC was observed. The total number of peritoneal exudate cells was significantly greater at 16, 24, and 40 hr after SRBC challenge when compared to that of vehicle-treated mice. The increased number of peritoneal cells reflected significant increases in both neutrophils and macrophages. Mac-1 + peritoneal cells were examined by two-color flow cytometric analysis on Days 0-3 after SRBC injection for expression of the activation markers F4/80 and I-A. The intensity of F4/80 fluorescence significantly decreased 24-72 hr following SRBC challenge, while fluorescence associated with I-A significantly increased at 72 hr. These changes are consistent with macrophage activation. TCDD did not significantly alter F4180 expression on Mac-1 + cells, whereas I-A expression was increased earlier on cells from TCDD-treated mice. However, TCDD treatment did not alter the antigen presentation function of peritoneal cells, assessed by their ability to induce the proliferation of SRBC-primed T cells in vitro. The antigen-presenting function of adherent spleen cells was also not altered by TCDD exposure. To test the hypothesis that an excess number of phagocytes in TCDD-treated mice were clearing the antigen more efficiently, leading to a smaller (e.g., suppressed) antibody response, we attempted to overcome TCDD suppression by increasing the amount of SRBC antigen used for challenge. However, the magnitude of the anti-SRBC response in TCDD-treated mice was not significantly altered by increasing the antigen challenge dose, suggesting that enhanced clearance of antigen by macrophage is not a mechanism for TCDD-induced suppression of the anti-SRBC response. The mechanism(s) for the enhanced inflammatory response and its relationship, if any, to TCDD immunotoxicity remain to be elucidated.

Cellular Responses of Oysters Infected with Haplosporidium nelsoni: Changes in Circulating and Tissue-Infiltrating Hemocytes

The protozoan parasite Haplosporidium nelsoni (MSX) elicits an inflammatory-type response in oysters, Crassostrea virginica. We assayed circulating hemocytes of oysters exposed to H. nelsoni to quantify the effects of parasitism, selection for resistance, and season on total and differential counts. All factors had a significant (P < 0.02) effect on total counts, but explained relatively little of the overall variance [season (12%) > selection (4%) > infection (2%)]. Circulating hemocyte densities increased with infection intensity in resistant animals, but were depressed in susceptible oysters with light infections. Counts in both groups were lowest in August and highest in May, at which times densities in susceptible oysters were reduced (P < 0.02) compared to those in resistant animals. No differences existed in November. Susceptible oysters may be more debilitated by infections than resistant animals, resulting in impaired circulation and depressed cell counts. The number of tissue-infiltrating hemocytes increased with infection intensity (P < 0.0001), but showed no statistically significant (P > 0.05) association with numbers of circulating hemocytes in individual oysters. Size-frequency analysis with a Coulter counter indicated that the proportion of large cells (presumed to be granular hemocytes) was lower (P < 0.0001) in susceptible oysters, which were also heavily infected, compared to resistant oysters, which had very few infections. The loss of granular hemocytes may stem from degranulation associated with tissue damage and inflammation. Present evidence suggests that the principal role of the hemocyte response in MSX disease is to plug lesions, remove debris, and repair tissues and that these functions may help oysters survive infection.

The ultrastructural architecture of the tissue/hard-tissue replacement interface

This investigation examined the tissue response and interfacial bonding between bone and hard-tissue replacement (HTR) using scanning (SEM) and transmission (TEM) electron microscopy. Twenty adult male Sprague-Dawley rats were anesthetized and a hole (1.0 mm deep by 2.0 mm wide) was drilled in the calvarium. Subsequently, HTR was implanted and the wound closed. The implants and surrounding tissues were removed at 7, 14, 28, and 56 days and prepared for examination by SEM or TEM. Scanning electron microscopic analysis revealed a typical inflammatory response that subsided by day 14. At that time, a fine layer of collagen fibrils (fibrous envelope) was observed covering the polymeric surface. Energy dispersive x-ray analysis (EDXA) showed no sign of mineralization. Ultrastructural analysis demonstrated that the fibrous envelope was bilaminar; it consisted of a relatively undifferentiated cellular layer adjacent to the polymer and an outer fibrous region. Scanning electron microscopic analysis of 28-day implants showed that osteoblasts had migrated onto the outer surface of the fibrous envelope and that calcification had been initiated as judged by EDXA. Electron microscopic examination confirmed previous observations of an undifferentiated cellular layer along the interfacial boundary, but also showed both macrophages and foreign-body giant cells. At 56 days, bone was observed to contact and cover the fibrous envelope surrounding the polymeric bead; however, EDXA showed that the fibrous envelope remained noncalcified. Transmission electron microscopic analysis revealed that the inner cellular layer was beginning to mature, as indicated by the presence of numerous cellular organelles. This maturation was accompanied by an increased incidence of macrophages as well as foreign-body giant cells. Within the time constraints of the experimental design, it is apparent that a bilaminar layer of cells and fibers remains between the HTR and the bone. Additional studies will be necessary, over extended time periods, to determine whether the bilaminar layer remains a constant feature between the HTR and the surrounding bone or whether this region is gradually supplanted by the ingrowing bone.

Decidual Activation in Parturition: Examination of Amniotic Fluid for Mediators of the Inflammatory Responsea

The accumulation of bioactive agents (characteristic of an inflammatory-type response) in amniotic fluid is common during term and preterm labor, viz., interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). In addition, prostaglandins, including PGE2, PGF2 alpha, and PGFM, also accumulate in amniotic fluid in some cases of term and preterm labor. From these observations, a number of critical questions arise. Namely, 1) what is the tissue source of origin of these agents?; 2) what are the stimuli that evoke this inflammatory response?; and, 3) are these bioactive agents of inflammation involved in the commencement of labor or else a natural accompaniment of the parturition process? It is reasonable to suspect that the decidua is activated during parturition as the membranes-decidua are exposed after cervical dilation to the vaginal/cervical secretions. Amnion and chorion laeve, in the human, are avascular tissues that produce PGE2 but not PGF2 alpha. Therefore, the accumulation of PGF2 alpha and PGFM in amniotic fluid during labor cannot be attributed to a fetal membrane origin. Moreover, the fetal membranes and decidua do not convert PGE2 to PGF2 alpha. In addition, the fetal membranes do not produce mature, i.e., secreted 17kD IL-1 beta. On the other hand, the decidua does produce PGF2 alpha and PGFM and is stimulated to do so by agents in the vaginal secretions, namely, bacterial endotoxin and IL-1 beta. After the fetal membranes and contiguous decidua are exposed during the time of cervical dilatation, these tissues are acted upon to cause 1) an influx of mononuclear phagocytes into the forebag compartment of the amniotic fluid; 2) to produce PGF2 alpha and PGFM; and 3) to produce cytokines, including IL-1 beta, IL-6, and TNF-alpha. Exposure of the fetal membranes-decidua to bioactive agents in vaginal/cervical secretions will effect an inflammatory response both in vivo and in vitro. We conclude that the accumulation of bioactive agents characteristic of the inflammatory response in amniotic fluid during term and preterm labor is usually an accompaniment of parturition and not its cause.

Otopathologic Correlates of the Continuum of Otitis Media

It has been our hypothesis that different types of middle ear effusions and the clinical manifestations with which they are associated represent the typical inflammatory response. Employing an animal model under controlled conditions, we present statistical evidence that change in the mucosa of the middle ear in otitis media can occur along a continuum, with early forms regressing to more chronic stages of the disease. We also demonstrate an increase in the thickness and a decrease in the permeability of the round window membrane in a longitudinal study of otitis media in the same animal model. Histopathologic changes in human temporal bones with otitis media with effusion or chronic otitis media are similar to the changes in the animal models. These results support a concept that all categories of otitis media (serous, purulent, mucoid, and chronic) represent different stages in a continuum of events.

Focal disruption of spermatogenesis in the testis of adult rats after a single administration of human chorionic gonadotrophin.

The effect of a single injection of 100 i.u. human chorionic gonadotrophin (hCG) upon the morphology of the rat testis was studied by light and electron-microscopy from 12-48 h after treatment. Twelve hours after injection of hCG, emigration of leukocytes occurred across the intertubular blood vessels and, both at this time and at 24 h, infiltrations of leukocytes were observed within the extracellular tissue spaces. Furthermore, 12 h after hCG, the seminiferous epithelium showed focal disruption of spermatogenesis involving germ cell degeneration and pyknosis. Focal damage to the seminiferous epithelium persisted at 24 h and 48 h after injection of hCG, the affected seminiferous tubules showing failure of spermiation, accumulation of extracellular vacuoles and degeneration or partial loss of spermatogonia and primary spermatocytes. The observations show that, after stimulation of the Leydig cells with hCG, the intertubular tissue exhibits an inflammatory-type response and this is associated with focal tissue destruction in the seminiferous tubules. It is concluded that a high dose of hCG exerts anti-spermatogenic effects upon the testis and raises the possibility of unexpected interference with tests of normal Leydig cell function in both laboratory and clinical investigations.

Macrophage activation enhances the human chorionic gonadotrophin-induced disruption of spermatogenesis in the rat.

The objective of this study was to examine the role of intertubular macrophages in modifying the response of the rat testis to stimulation by human chorionic gonadotrophin (hCG). The phagocytic activity of macrophages was stimulated by a unilateral intratesticular injection of polystyrene latex beads. Latex beads were engulfed by the resident macrophages and retained within their cytoplasm. Contralateral testes received injection of vehicle alone. A group of control rats was killed 3 days later; other groups received 100 IU hCG s.c. and the morphological and functional responses of the testes were examined 12, 24 and 48 h later. Spermatogenesis was unaffected in control rats, whereas in the testes of all hCG-treated rats leukocytes infiltrated into the intertubular tissue and the seminiferous tubules exhibited focal disruptions of spermatogenesis which were more severe in testes containing activated macrophages. Spermatogenic disruption was dependent upon the stage of the spermatogenic cycle, with the maximum tubule degeneration occurring at or near stages III and IX-XI. However these changes were not a consequence of androgen deprivation, since no consistent correlation was demonstrated between alterations in testosterone levels in testicular interstitial fluid and the accompanying damage to germ cells. It is concluded that hCG alone or in combination with activated macrophages induces an inflammatory-type response of the intertubular tissue and localized degeneration of the seminiferous epithelium. The antispermatogenic effects of hCG may have important implications for in-vivo investigations of Leydig cell function in laboratory animals and for the efficacy of hCG administration used in the clinical treatment of male hypogonadism.

Prolongation of pig-to-dog renal xenograft survival by modification of the inflammatory mediator response.

The pathogenesis of hyperacute renal rejection consists of a nonspecific effector cascade that invokes most of the components of a typical acute inflammatory response. Platelet-activating factor (PAF) represents the most recent and perhaps the most significant mediator and promoting agent of this phenomenon. These studies evaluated SRI 63-441, a novel, synthetic, and the most potent PAF receptor antagonist available, alone and in combination with other prostanoids, for their ability to influence this response and to prolong renal xenograft survival and function in a model of pig-to-dog heterotransplantation. Inhibition of PAF by SRI 63-441 alone, at the dosage and schedule used in these experiments, did not significantly prolong xenograft survival or function. However, the combination of SRI 63-441 with either prostacyclin (PGI2) or prostaglandin E1 (PGE1) infusion demonstrated significant synergism, and resulted in a 6-9-fold increase in kidney survival and a 3-20-fold increase in urine output. Neither PGI2 nor PGE1 infusions alone significantly influenced this xenograft model. Electromagnetic flow studies demonstrated significantly delayed diminution in renal artery blood flow in the combination-treated animals. Serial and end-stage histologic examination of kidneys receiving combination therapy demonstrated a delayed onset of the pathologic deterioration and an overall amelioration of the entire process. These studies demonstrate that significant abrogation of a rapid and violent form of hyperacute rejection can be achieved solely by the pharmacologic manipulation of the inflammatory mediator response.

Allergic and nonallergic factors in upper and lower airway disease.

The specific allergic and nonallergic mechanisms that prevail in diseases of the upper and lower airways, e.g., rhinitis and asthma, are reviewed. These mechanisms and diseases are probably not more prevalent in wind players than in others, but they may significantly impair a musician’s capabilities. Specific allergic triggers include pollens, molds, dusts, and danders; and the typical immediate inflammatory response to these is mediated by IgE. There is a growing understanding of late-phase reactions, which are triggered by IgE but which occur four to 12 hours after antigen exposure. Specific allergic responses may occur with or without nonspecific, non-IgE reactions, which include responses to a wide variety of irritants including cold air, particulates, and infections. There is a growing realization that host responses to specific allergens and nonspecific irritant factors can influence and accentuate each other. Treatment should be directed toward identification and avoidance of both kinds of triggers. Immunotherapy is sometimes required.

Abnormalities affecting structure and function of the bladder and urethra

Gene expression in healthy synovium remains poorly characterised. Thus, synovial functional activity changes associated with osteoarthritis (OA) are difficult to define. This study sought to identify differentially expressed genes (DEG) of end-stage OA and assess the influence of OA risk factors on these DEG.Anonymised patient clinical data and x-ray images were analysed. Osteoarthritic and non-osteoarthritic patients with soft tissue or traumatic knee injuries were matched for body mass index (BMI) and sex. Tissue samples were partitioned for immunocytochemistry (IHC) and microarray analysis. Multiple bioinformatics applications were utilised to determine changes in functional and canonical pathway activation.Age, disease-modifying injections and hypertension were confounding factors between patient groups. Inflammation was present in all tissues. Cartilage debris and inflammatory aggregates were noted in many osteoarthritic patient tissues. IHC and expression analyses revealed upregulation of synoviolin 1 (SYVN1) in osteoarthritic synovium. Significant differential expression was noted in 2084 genes. Osteoarthritic synovium displayed a significant upregulation of 95% of DEG coding for proteins, relative to non-osteoarthritic synovium tissues. Unfolded protein response (UPR)-related genes were upregulated in osteoarthritic synovium; gene expression of molecules within many canonical pathways including protein ubiquitination and UPR pathways was modified by BMI and sex.The synovium of all three pathologies exhibited elements of an inflammatory response. Cartilage debris, age, BMI and sex influence DEG of osteoarthritic synovium. UPR pathway is the top deregulated canonical pathway identified in osteoarthritic synovium regardless of BMI and sex, while typical OA-associated inflammatory and matrix gene responses were minimal.

Leishmania species: Comparative ultrastructure of experimental nodules and diffuse human cutaneous lesions in American leishmaniases

Experimental nodules of American leishmaniases were obtained by inoculating 0.1–1 × 10 5 amastigotes into the dorsum of the hindpaws of golden hamsters and of C57B1/6J mice. The amastigotes were obtained by biopsy of lesions in six human cases of cutaneous leishmaniases and were serially maintained in golden hamsters and in a fetal calf serum-containing medium. Human nodules were obtained by biopsy from several patients with diffuse cutaneous leishmaniases, always prior to treatment. Within the same host species, no ultrastructural differences were seen in the tissue response to isolates of Leishmania mexicana, L. brasiliensis, or L. garnhami, nor were there differences between the host species in response to a particular isolate of the genus Leishmania. The typical inflammatory response was a macrophage granuloma with abundant polymorphonuclear neutrophils, some eosinophils, and plasma cells. Simple human cutaneous leishmanial lesions, as well as experimental nodules in regression, show many fibroblasts, much collagen fiber, but very few parasites. In typical lesions, parasites occurred within macrophage phagolysosomes, within distended lacunar cells, and in the intercellular spaces. Leishmaniae strongly adhered to parasitophorous vacuoles by a site of their plasma membrane directly opposite the flagellum, and the host cell cytoplasm close to the adherence site became highly vacuolated. In most cases the intra- and extracellular parasites show normal morphology, which suggest the inability of phagocytic cells to attack them.

The granuloma pouch: an in vivo model for pharmacokinetic and chemotherapeutic investigations. I. Biochemical and histological characterization.

The "granuloma pouch" model in rats was evaluated on the basis of biochemical, haematological and histological factors. Seven days after formation of the pouch following the intramuscular injection of air and a mixture of 1% croton oil in olive oil as an irritant, the pouch was filled by approximately 5 ml of haemorrhagic exudate. Biochemical assessment of the exudate revealed that its main characteristics were increased lactate dehydrogenase levels as well as increased alpha 2- and gamma-globulin fractions. Histological sections of the surrounding tissue showed a typical granulomatous inflammatory response. The granuloma pouch can therefore be characterized as a local, chronic inflammation caused by the creation of a body cavity. The biochemical data of the pouch exudate were compared with those of human wound fluid obtained after surgery; since the values were in very good agreement, it is assumed that the granuloma pouch model reflects the clinical situation in inflamed wound cavities following the extirpation of organs.

The inflammatory response to endotoxin.

A typical inflammatory response resulted from the intravenous injection of endotoxin (E. coli) into living rabbits. Each rabbit was studied at three levels: the microvasculature and supporting tissue in the ear chamber was observed microscopically (up to X200) before, during, and at regular intervals following the injection of endotoxin; leucocyte and platelet counts were made periodically throughout each experiment; and tissue samples for histological study were obtained from each rabbit prior to death. The animal was anaesthetised before histological samples were secured. Within minutes after the intravenous injection of endotoxin, leucocytes were observed sticking to the endothelial cells lining the venules and the arterioles. Emboli appeared in the microcirculation within 10 min. Swelling of the microvascular endothelial cells was evident at 1 hr; oedema and extravasation of the cellular elements followed. The rectal temperature and leucocyte and platelet counts all fell within 10 min. of endotoxin. Histological examination of tissue from the ear chamber and visceral organs showed inflammatory changes. Congestion of the microvasculature, swelling of the endothelial cells, and margination and migration of neutrophils were common histological features in all organs. The earliest cells affected appeared to be the leukocyte and platelet.

Pathogenesis of papain-induced emphysema in the hamster.

In an effort to determine the mechanism of papain action in causing an emphysema-like lesion in hamsters, the number and types of cells and the activities of two lysosomal enzymes in the lung were determined after papain exposure. Three and four weeks after a 3-h exposure to an aerosol of 3% papain the following alterations in lung structure and function were observed: (1) the mean linear intercept, or average distance between adjacent alveoli, was increased; (2) the internal surface area declined; (3) the dynamic compliance was elevated at low breathing frequencies. The numbers of cells present free in the lung increased from a control value of 2.0 +/- 0.2 x 10 (6) to 6.6 +/- 0.5 x 10 (6) 5 days after exposure. The free beta-glucuronidase, alysosomal enzyme, likewise increased over threefold during the first 3 days after exposure. These results are consistent with the hypothesis that papain induces an inflammatory-type responses, and this may be in part responsible for inducing the lesion.