Services of thanksgiving at the end of gross anatomy courses: a unique task for anatomists?
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Anatomy↗
Biomedical subjects
T Tschernig
Publications and source records attributed to T Tschernig.
Fc gamma RIII-mediated production of TNF-alpha induces immune complex alveolitis independently of CXC chemokine generation.
We recently demonstrated a codominant role of C5aR and FcgammaRIII in the initiation of IgG immune complex-mediated inflammation in mice. In this study, we investigated the relative contribution of FcgammaRIII in the generation of several cytokines during experimental hypersensitivity pneumonitis/alveolitis in vivo. Induction of immune complex-alveolitis in C57BL/6 mice resulted in strong accumulation of neutrophils into the lung and enhanced chemotactic activity within bronchoalveolar lavage fluid accompanied by an increased production of the proinflammatory cytokines TNF-alpha and IL-1beta as well as the ELR-CXC chemokines macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC). FcgammaRIII-deficient C57BL/6 mice (FcgammaRIII(-/-)) showed a marked reduction of the inflammatory response due to decreased production of TNF-alpha, IL-1beta, and MIP-2. Results obtained in C57BL/6 mice either lacking the TNF-alpha class I receptor (TNF-alphaRI(-/-)) or treated with neutralizing anti-TNF-alpha mAb demonstrated an essential contribution of TNF-alpha for mediating IL-1beta release, neutrophil influx, and hemorrhage. Surprisingly, MIP-2 and KC chemokine levels remained largely unaffected in TNF-alphaRI(-/-) mice or after functional inhibition of TNF-alpha. These data suggest that in immune complex alveolitis, the activation of FcgammaRIII may induce divergent downstream effector pathways with TNF-alpha acting independently of CXC chemokines to trigger the inflammatory response in C57BL/6 mice.
Alveolitis, Extrinsic Allergic↗
The numbers of leukocyte subsets in lung sections differ between intercellular adhesion molecule-1-/-, lymphocyte function-associated antigen-1-/- mice and intercellular adhesion molecule-1-/- mice after aerosol exposure to Haemophilus influenzae type-b.
In order to investigate the role of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) in pulmonary immunological processes, leukocyte populations were stained immunohistochemically on cryostat lung sections of ICAM-1-/- and LFA-1-/- mice. A further group of ICAM-1-/- mice was exposed to Haemophilus influenzae type-b (Hib) 24 h before being sacrificed. Comparison of the numbers of leukocytes in these groups revealed different behaviors of the leukocyte subsets: granulocytes were significantly increased in all three groups. Lymphocytes were increased in ICAM-1-/- mice, while there was no significant difference in LFA-1-/- and even a decrease in ICAM-1-/- mice after Hib exposure. Neither in ICAM-1-/- nor in LFA-1-/- mice did macrophages and dendritic cells (DCs) show significant differences to control animals. After Hib exposure, a significant elevation of DCs was observed. The following conclusions can be drawn: (1) all investigated leukocyte subsets can use ICAM-1- and LFA-1-independent pathways in the lungs of mice; (2) the pathways used by the leukocytes are cell-type specific; (3) ICAM-1 plays an important role in the enhanced recruitment of lymphocytes during Hib challenge in the lung; and (4) the alternative migratory mechanisms are able to compensate for the absence of ICAM-1 or LFA-1 or even lead to increased cell numbers. This overcompensation can be seen as a result of a balance between active alternative migratory mechanisms, which takes place in the absence of ICAM-1 or LFA-1.
Aerosols↗
Evaluation of the medical curriculum: why, when, by whom and for whom should questionnaires be used.
The undergraduate medical curriculum has been modified or even totally reorganized in many countries in recent years, and there are plans to make departmental budgets and the salaries of university professors partially dependent on the outcome of teaching. Questionnaires are often used in such situations as a means of curriculum evaluation. Based on our own experience such evaluations should be done not only during and immediately after a course in the curriculum, but also at later time points, e.g., at the end of the undergraduate and also the postgraduate phase. The clinical relevance of lectures and courses can only be graded adequately after some years of clinical experience. Gross anatomy was graded top at all time points evaluated and reached higher levels of 'clinical relevance' than other typical preclinical and even clinical subjects. Efforts should be made to obtain a high response rate for representative results. After modifying parts of a course detailed questionnaires should also include space for students' suggestions. The results of such evaluations are not only relevant to the head of department as feedback on the individual lecturers but also important for the curriculum committee and the dean. Anatomists should utilize these evaluations to improve teaching.
Anatomy↗
Local proliferation contributes to lymphocyte numbers in normal lungs.
Lymphocytes in the bronchoalveolar lavage fluid (BAL) are increased in many lung diseases, which might be an indicator for protective reactions or pathology. Higher lymphocyte numbers at distinct organ sites may be due to a number of reasons such as increased entry, increased proliferation, reduced apoptosis or reduced exit. It is not known whether lymphocyte numbers are influenced by local proliferation in the healthy lung. Therefore, the proliferation of lymphocytes was studied in vivo in different lung compartments of healthy rats: the marginal vascular pool, the interstitial pool and the bronchoalveolar pool. Bromodeoxyuridine (BrdU) was used as an S-phase proliferation marker. The cells were obtained 1 h and 24 h after i.v. injection of BrdU. The labeled cells and their phenotypes were determined by immunocytochemistry, since it was not possible to use flow cytometry because of the low numbers. In the lung compartments 0.7-1.5% of all nucleated cells were found to be BrdU+, whereas 24 h later this increased to 3.2-5.7%. The frequency of BrdU+ T cells was significantly higher in the lung compartments compared to the blood, with the maximum in the marginal vascular pool. Local proliferation of lymphocytes involved mainly CD8+ T cells. Thus, local proliferation plays a role in the number and composition of lymphocytes in the healthy normal lung.
Animals↗
Similarities and differences in lectin cytochemistry of laryngeal and tracheal epithelium and subepithelial seromucous glands in cases of sudden infant death and controls.
BACKGROUND: It has been speculated that non-specific defence mechanisms of the epithelium and subepithelial seromucous glands play a role in the larynx and lungs in cases of sudden infant death. METHODS: The larynx and trachea from five children who had died of sudden infant death (SID) syndrome and five control cases of comparable age were compared for the presence of lectin binding sites (12 different lectins tested). RESULTS: The secretory product of mucin producing cells contained carbohydrates including galactose and sialic acids. Binding sites for fucose and N-acetyl-galactosamine were only present in some of the specimens and distribution revealed no correlation between cases of SID and controls. Epithelial cells and serous cells of seromucous glands contained binding sites for sialic acid in cases of SID and controls. Moreover, binding sites for mannose were detected in these cells but were only present in SID cases. The difference between the SID and control groups as to the presence/expression of concanavalin A was highly significant. CONCLUSIONS: It is suggested that mucus hypersecretion in SID occurs in response to bacterial toxins or viral infection and is not specific. The different binding sites for mannose in cases of SID and controls could indicate differences in the production of antimicrobial peptides. A disturbed expression pattern of antimicrobial peptides in children who later succumb to SID could be responsible for an imbalance of the local microflora with a higher density of microorganisms on the mucosa. Further studies are required to elucidate the pattern of expression of antimicrobial peptides in subsequent SID victims.
Binding Sites↗
Dendritic cells in the mucosa of the human trachea are not regularly found in the first year of life.
BACKGROUND: Dendritic cells (DCs) in the mucosa of the respiratory tract might be involved in the early development of pulmonary allergy or tolerance. To date, little is known about when the first DCs occur in human airways. METHODS: Specimens of the distal trachea from patients who had died from sudden death in the first year of life (n=29) and in older age groups (n=59) as well as from those who had died from respiratory tract infections in the first year of life (n=8) were examined by immunohistochemistry. Transmission electron microscopy was performed in additional samples from two adults. RESULTS: In the sudden death subgroup DCs were absent in 76% of those who died in the first year of life but were present in 53 of the 59 older cases. All infants who had died of respiratory infectious diseases had DCs in the tracheal mucosa. CONCLUSIONS: Mature DCs are not constitutively present in the human tracheobronchial mucosa in the first year of life, but their occurrence seems to be triggered by infectious stimuli. These data support the hypothesis that DCs play a crucial role in immunoregulation in early childhood.
Adolescent↗
Cytokine profile of bronchoalveolar lavage-derived CD4(+), CD8(+), and gammadelta T cells in people with asthma after segmental allergen challenge.
T cell-derived cytokines play an important role in the pathogenesis of allergic asthma, but little is known about the cytokine profile of their different subsets. The aim of the present study was to investigate the cytokine production potential of CD4(+), CD8(+), or gammadelta(+) T cells derived from the bronchoalveolar space of mild atopic asthmatic subjects (n = 11) and nonatopic control subjects (n = 9) before and 24 h after segmental allergen challenge. The cytokine production was determined using the technique of intracellular cytokine detection by flow cytometry. Comparing asthmatic with control subjects we found no difference in the percentage of CD4(+), CD8(+), or gammadelta T cells in the bronchoalveolar lavage fluid before and after allergen challenge. Before allergen challenge the proportion of cells producing the cytokines interferon (IFN)-gamma, interleukin (IL)-2, IL-4, IL-5, and IL-13 was not different in CD4(+) and CD8(+) cells. The major difference between the groups was an increased percentage of positive-staining cells for the T helper-(Th)2-cytokines IL-5 and IL-13 in the gammadelta T-cell subset. After allergen challenge, all T-cell subsets revealed a decreased proportion of cells producing the Th1-type cytokines IFN-gamma and IL-2. The percentage of IL-4- and IL-5-positive cells did not change in all subsets, and there was a decreased proportion of IL-13- positive cells in the CD4(+) subset. These findings indicate an increased Th2-cytokine profile in gammadelta T cells. After allergen challenge, the dysbalance between Th1 and Th2 cytokines was further accentuated by a reduction in Th1 cytokine-producing T cells.
Adult↗
Effects of macrophage-CSF on pulmonary-macrophage repopulation after bone marrow transplantation.
Pulmonary infections are important causes of morbidity and mortality in immunosuppressed patients after transplantation. After experimental irradiation and syngeneic bone marrow transplantation in mice, macrophages show reduced repopulation in the lung compared with that in other tissues. Macrophages are major microbicidal immune effector cells in host pulmonary defense. Therefore, we examined the role of locally applied cytokines for macrophage repopulation in the lung. An accelerated repopulation of macrophages in the lung was observed after intranasal application of macrophage-colony stimulating factor (M-CSF), but this effect was not enhanced by a combination of M-CSF with interleukin (IL)-3. Local proliferation contributed to this effect. Macrophages in the lung tissue of M-CSF-treated mice displayed greater secretion of IL-6, whereas M-CSF treatment did not enhance the gene expression of other macrophage-specific chemokines. The role of M-CSF treatment was determined in pulmonary murine cytomegalovirus infection using an irradiation/reconstitution model. The M-CSF treatment had no effect on virus load in the lung tissue. However, phosphate-buffered saline-treated mice seemed to develop stronger inflammation after viral infection than M-CSF-treated mice. We conclude that local M-CSF treatment modulates cellular inflammation in the lung during immunosuppression.
Administration, Intranasal↗
Tissue distribution of components of the insulin-like growth factor system in sudden infant death and controls.
Growth factors may be involved in sudden infant death (SID). Among these factors, the insulin-like growth factor (IGF) family is important in human fetal and perinatal organ growth and development. In order to detect probable differences in the occurrence and distribution of components of the IGF system, tissue samples from liver, lung, skin, parotid and thyroid gland, gut and cerebellum from SID children (n=9) and controls (n=6) aged between 14 and 258 days of life (mean 105 days) were stained immunohistochemically using antibodies against IGF-I, IGF-II and their specific IGF-I-receptor (IGF-IR). In contrast to controls in hepatocytes of SID children a reduction or an absence of immunoreactivity for IGF-I and IGF-IR and a weaker staining for IGF-II was detected. IGF-II in smooth muscle layers in the gut and IGF-I in epithelial cells in intestinal specimens also showed a reduced immunoreactivity in SID children and those who died traumatic deaths. In the other organs examined no significant differences in the distribution of the insulin-like growth factor system between the groups could be detected, indicating that in SID children no fundamental differences or alterations in the physiology of the IGF system occur. Because of the decreased immunostaining of IGFs in the liver and intestine of SID cases, a local dysregulation may be discussed.
Autopsy↗
Stereological quantification of carboxyfluorescein-labeled rat lung metastasis: a new method for the assessment of natural killer cell activity and tumor adhesion in vivo and in situ.
The function of natural killer (NK) cells is often studied by assessing in vitro levels of NK cell mediated lysis of target cells, or by assessing in vivo levels of lung tumor cell retention or metastatic colonization of intravenously injected tumor cells. However, these methods do not permit direct quantification and visualization of NK cells and their targets in vivo and in situ. Here, a new approach is described to visualize effector-to-target interactions as well as to estimate total numbers of targets in the lung, in vivo and in situ. MADB106 tumor cells were vitally labeled using carboxyfluorescein (CFSE) and intravenously (i.v.) injected into Fischer 344 rats (10(6) cells/rat). This mammary adenocarcinoma derived cell line is syngeneic to the inbred Fischer 344 rat and highly sensitive to NK cell activity in vivo. Effector-to-target interactions were visualized by immunostaining. Using the optical fractionator method, total numbers of CFSE-labeled MADB106 tumor cells were estimated in the left lung of the animals 5 min after tumor inoculation. To further demonstrate the usefulness of this approach in reflecting in vivo processes, rats were inoculated with MADB106 cells and simultaneously with a single i.v. bolus of either 1 microg/kg adrenaline or saline. Both lungs were removed 5 min later. Adrenaline caused a significant 80% reduction in the total number of lung CFSE-labeled MADB106 tumor cells, suggesting a rapid modulation of metastasis by stress hormones. This new approach facilitates the monitoring of effector-to-target interactions and the quantification of immune cell function or tumor adhesion in vivo and in situ.
Adenocarcinoma↗
Transplantation of H-2Kb-transgenic adrenocortical cells in the mouse having undergone an adrenalectomy: functional and morphological aspects.
BACKGROUND: A new model of cellular adrenocortical transplantation after bilateral adrenalectomy in the mouse was established. This model was used to study the effects of the expression of the transgenic MHC class I molecule H-2K(b) (Kb) on graft survival and morphologic features, corticosterone secretion, and the possibility of tolerance induction in the recipient. METHOD: A single cell suspension of purified adrenocortical cells was grafted under the kidney capsule of B10.Br (H-2k) mice having adrenalectomies. Syngeneic, fully MHC-mismatched, and MHC class I-incompatible Kb-transgenic mice served as donor strains. To analyze graft function, urinary excretion and serum levels of corticosterone were monitored over 100 days. Tolerance induction in the graft recipients of Kb-transgenic and third party skin grafts was tested on day 50 after adrenocortical transplantation. Histological sections of the adrenocortical grafts were obtained on day 100. RESULTS: Recipients of syngeneic and Kb-transgenic grafts displayed pretransplant corticosterone levels on days 20, 50, and 100 and ACTH-stimulated serum corticosterone levels similar to those of controls on day 100 after adrenocortical transplantation. In contrast, in recipients of fully MHC-mismatched grafts, corticosterone excretion was significantly reduced. In this group, 4 of 7 mice did not survive. Syngeneic skin grafts survived indefinitely in recipients of syngeneic and Kb-transgenic adrenocortical grafts, whereas Kb-transgenic and fully MHC-mismatched skin grafts were acutely rejected. Tissue sections of the adrenocortical grafts revealed vascularized cell conglomerates in syngeneic and Kb-transgenic grafts without infiltrations of mononuclear cells. Furthermore, a differentiation similar to adrenocortical organization was partly found. CONCLUSION: In conclusion, a model of cellular adrenocortical transplantation was established. The results show that syngeneic transplantation resulted in physiological corticosterone levels early after transplantation, whereas fully MHC-incompatible grafts were rejected. Recipients of Kb-transgenic grafts showed unimpaired adrenocortical function, but did not tolerize toward Kb-transgenic skin grafts. Possible mechanisms include a local immunomodulatory effect of glucocorticoids secreted by the graft and a low immunogenicity of the relatively small numbers of transplanted cells.
Adrenal Cortex↗
Emotional reactions of medical students to dissecting human bodies: a conceptual approach and its evaluation.
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Anatomy↗
A codominant role of Fc gamma RI/III and C5aR in the reverse Arthus reaction.
Recent attempts to specify the relative contribution of FcR and complement in various experimental systems of immune complex disease have led to opposing conclusions. As concluded in IgG FcRgamma-/- mice, manifestation of disease is almost exclusively determined by FcgammaR on effector cells, arguing for a minor role of complement. In contrast, data obtained with C5aR-/- mice suggested that, dependent on the tissue site, complement is more important than FcgammaR. In this paper, we demonstrate that, in response to IgG immune complex formation, FcgammaRI/III- and C5aR-mediated pathways are both necessary and only together are they sufficient to trigger the full expression of inflammation in skin and lung. Moreover, both effector systems are not entirely independent, suggesting an interaction between FcgammaR and C5aR. Therefore, FcgammaR-mediated responses can be integrated through C5aR activation, which may explain why these two receptor pathways have previously been considered to dominate each other.
Animals↗
Blockade of leucocyte function-associated antigen-1 (LFA-1) decreases lymphocyte trapping in the normal pulmonary vasculature: studies in the isolated buffer-perfused rat lung.
Adhesion molecules regulate the migration of lymphocytes in lymphoid and non-lymphoid organs. In the lung, little is known about lymphocyte sticking and migration through the pulmonary vascular endothelium in physiological or pathological situations. Therefore the isolated buffer-perfused rat lung was used to investigate the mobilization of lymphocytes out of the normal lung into the venous effluent and to the bronchoalveolar space. The lymphocyte subset composition was characterized in the venous effluent, the lung tissue and the bronchoalveolar lavage (BAL) using immunocytology. Lymphocytes continuously left the normal lung at a total of 5.0 +/- 0.7 x 106 cells within the first hour of perfusion. The injection of 200 x 106 lymphocytes via the pulmonary trunk increased the venous release of lymphocytes by 170%. To investigate the effect of LFA-1 and CD44 on the adhesion of lymphocytes to the pulmonary endothelium, lymphocytes preincubated with an anti-LFA-1 MoAb, which blocks the interaction of LFA-1 and intercellular adhesion molecule-1 (ICAM-1), or lymphocytes preincubated with an anti-CD44 MoAb, were injected. The injection of LFA-1-blocked lymphocytes led to an increase by 70% of injected cells recovered in the perfusate within the first hour, whereas anti-CD44 treatment of injected lymphocytes had no effect. The LFA-1-blocked lymphocytes showed higher numbers of T and B cells in the effluent. Thus, the present experiments demonstrate that LFA-1 influences the trapping of lymphocytes in the vasculature of the healthy rat lung.
Animals↗
[Recruitment of immunocompetent cells in a transplanted lung is not impaired despite incompletel reinnervation].
BACKGROUND: It is not clear whether surgical intervention during lung transplantation which includes cutting vegetative nerves, lymphatic vessels and bronchial arteries, leads to alterations in immune responses. Thus, it was studied in an animal model whether an induced pulmonary immune reaction after syngenic lung transplantation was impaired without the influence of immunosuppression and rejection. The recruitment of leukocytes and the status of reinnervation was examined. METHODS: Syngenic transplantation of the left lung was performed in Lewis rats without rejection and therefore without immunosuppressive therapy. In a subgroup of animals host and donor leukocytes were distinguished. An ovalbumin (OVA)-specific pulmonary immune response was induced four months after transplantation. Bronchoalveolar lavage (BAL) and interstitial leukocytes were examined using flow cytometry and immunocytology, comparing the right lung and the grafted left lung. Immunohistology was performed to detect nerve fibers on cryostat sections. RESULTS: An induced cellular inflammation was observed in the right host lung as well as in the grafted left lung. However, the CD4 T cell numbers in the BAL were increased in the left lung. Single donor-type leukocytes could still be observed four months after transplantation. A partial reinnervation was found. CONCLUSIONS: The recruitment of immune cells into the lung interstitium and bronchoalveolar space of grafted lungs is not impaired. The incomplete reinnervation has no influence on leukocyte recruitment.
Animals↗
Lymphocytes migrate from the blood into the bronchoalveolar lavage and lung parenchyma in the asthma model of the brown Norway rat.
Lymphocyte migration from the blood into the lung has been suggested as being responsible for the increase of lymphocytes, in particular CD4 T cells, in the bronchoalveolar lavage (BAL) and bronchial mucosa in human asthma, but so far there has been no direct proof. We studied lymphocyte immigration and lymphocyte subpopulations in three lung compartments in ovalbumin (OVA)-sensitized and -challenged brown Norway (BN) rats. Increased numbers of CD4 and interleukin 2 (IL-2) receptor-positive T cells were found in the BAL and lung parenchyma in treated animals, but also increased numbers of CD8 T cells, B cells, and natural killer (NK) cells. For direct proof of lymphocyte migration from the blood into the lung, leukocytes were labeled with a fluorescent dye, 5- (and 6-) carboxyfluorescein-diacetate-succinimidyl-ester (CFSE), and injected intravenously immediately prior to OVA aerosol challenge. One day after challenge the number of CFSE(+), i.e., newly immigrated lymphocytes, was determined by flow cytometry gated on the lymphocyte cluster. A 15 times (1.5 times) higher number of CFSE(+) lymphocytes was found in the BAL (the lung parenchyma) of treated animals in comparison with control rats. In the BAL 51.8% of CFSE(+) cells were CD4-positive (parenchyma 72.7%) and 29.4% IL-2 receptor-positive (parenchyma 34.2%). There was no difference whether the leukocytes for labeling and injection were obtained from untreated or from OVA-sensitized donor animals. Our data show that lymphocyte immigration is at least in part responsible for the increase in lymphocyte numbers in the BAL and lung parenchyma in this animal asthma model.
Animals↗
Interleukin 16 and T-cell chemoattractant activity in bronchoalveolar lavage 24 hours after allergen challenge in asthma.
IL-16 has been shown to be one of the earliest CD4(+) cell chemoattractants present in BAL 4-6 h after antigen challenge but little is known about its persistence and biological activity after 6 h. We determined the concentration of IL-16 using ELISA and the T-cell chemoattractant activity using a modified Boyden chamber assay in unconcentrated BAL fluid from 13 patients with mild asthma and 9 nonatopic control subjects at baseline and 24 h after segmental allergen or saline challenge. Furthermore, the percentage of IL-16-producing T cells was determined in the different samples of BAL fluid using a flow cytometric intracellular cytokine assay. Although no substantial levels of IL-16 protein were detectable in BAL fluid from control subjects and patients with asthma at baseline and after saline challenge, IL-16 concentrations were significantly elevated in patients with asthma after allergen challenge (median, 97 pg/ml; range, 38-362 pg/ml; p < 0.01). Furthermore, there was an increased T-cell chemoattractant activity after allergen challenge in patients with asthma (p < 0.01), which could be blocked by preincubation with anti-IL-16 antibodies and which correlated significantly with the IL-16 protein levels (R = 0.90, p < 0.01) and with the level of Fas ligand expression on BAL CD4(+) cells (R = 0. 80, p < 0.05). A high percentage (mean 70-90%) of CD4(+) and CD8(+) cells stained positively for IL-16 in both patients with asthma and control subjects without differences after allergen or saline challenge. These data demonstrate that the increased chemotactic activity for T cells in patients with asthma is mainly attributable to IL-16. Although T cells by themselves are able to produce IL-16, other cells, such as epithelial cells, have to be considered as further sources for this cytokine in patients with asthma.
Adult↗