RESUMEN
Essentials Tissue factor (TF) represents a central link between hemostasis and inflammation. We studied the roles of myeloid and airway epithelial TF in acid-caused acute lung injury (ALI). TF on myeloid cells displays a non-coagulatory role regulating the inflammatory response in ALI. Airway epithelial TF contributes to hemostatic functions, but is dispensable in ALI pathogenesis. SUMMARY: Introduction Acute lung injury (ALI) is a life-threatening condition characterized by damaged alveolar-capillary structures and activation of inflammatory and hemostatic processes. Tissue factor (TF) represents a crucial link between inflammation and coagulation, as inflammatory mediators induce myeloid TF expression, and TF initiates extrinsic coagulation. Objective As pulmonary inflammation stimulates TF expression and TF modulates immune responses, we aimed to elucidate its impact on ALI. In particular, we wanted to distinguish the contributions of TF expressed on airway epithelial cells and TF expressed on myeloid cells. Methods Mice with different cell type-specific TF deficiency and wild-type littermates were intratracheally treated with hydrochloric acid, and leukocyte recruitment, cytokine levels, thrombin-antithrombin (TAT) complexes and pulmonary protein-rich infiltrates were analyzed. Results Our data demonstrate that a lack of epithelial TF did not influence acute responses, as bronchoalveolar neutrophil accumulation 8 h after ALI induction was unaltered. However, it led to mild, prolonged inflammation, as pulmonary leukocyte and erythrocyte numbers were still increased after 24 h, whereas those in wild-type mice had returned to basal levels. In contrast, myeloid TF was primarily involved in regulating the acute phase of ALI without affecting local coagulation, as indicated by increased bronchoalveolar neutrophil infiltration, pulmonary interleukin-6 levels, and edema formation, but equal TAT complex formation, 8 h after ALI induction. This augmented inflammatory response associated with myeloid TF deficiency was confirmed in vitro, as lipopolysaccharide-stimulated TF-deficient alveolar macrophages released increased levels of chemokine (C-X-C motif) ligand 1 and tumor necrosis factor-α as compared with wild-type macrophages. Conclusion We conclude that myeloid TF dampens inflammation in acid-induced ALI.
Asunto(s)
Lesión Pulmonar Aguda/prevención & control , Células Epiteliales/metabolismo , Ácido Clorhídrico , Pulmón/metabolismo , Macrófagos Alveolares/metabolismo , Neumonía/prevención & control , Tromboplastina/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/metabolismo , Animales , Antitrombina III/metabolismo , Coagulación Sanguínea , Células Cultivadas , Quimiotaxis de Leucocito , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/inmunología , Predisposición Genética a la Enfermedad , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Macrófagos Alveolares/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila , Péptido Hidrolasas/metabolismo , Fenotipo , Neumonía/inducido químicamente , Neumonía/inmunología , Neumonía/metabolismo , Edema Pulmonar/inducido químicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/prevención & control , Tromboplastina/deficiencia , Tromboplastina/genética , Factores de TiempoRESUMEN
OBJECTIVE: Arthritis is frequently seen in human lupus, but rarely in lupus models. Pristane-induced lupus (PIL) can be induced in various mouse strains such as BALB/c and C57BL/6. We herein characterize clinical and histological features of arthritis in the context of systemic lupus and provide a prudent comparison with models of rheumatoid arthritis (RA). METHODS: A total of 57 BALB/c mice received pristane (PIL group) and were analyzed for serum autoantibodies (anti-chromatin-, -histone, -Sm, -dsDNA), as well as for clinical features and histopathology of joints, lungs and kidneys. Joint pathology was quantified by image analysis and tissue cytometry. Ten C57BL/6 mice (Bl/6-PIL) and historical groups of two different RA models were analyzed accordingly. RESULTS: In BALB/c PIL, clinical arthritis started at three months, occurred finally in 79% of PIL (but not in controls, p<0.001) and correlated with areas of inflammation, erosion, cartilage damage, osteoclast numbers and total severity score (for all: r>0.7, p<0.001). After eight months, 58% of PIL (but no controls, p<0.001) had mild-erosive arthritis. In contrast to RA, the most frequent inflammatory cell type of the pannus was granulocytes (17.7%), PIL had lower numbers of osteoclasts, erosions rarely affected both layers of the cortical bone and there was no progression to complete joint destruction (even after one year of observation). Serum autoantibodies (auto-abs) preceded arthritis and became significantly elevated in all PIL; affected joints showed increased deposits of IgG (and IgM) within the inflammatory tissue, indicative of an ab-mediated process. PIL mice with arthritis also showed signs of pulmonary (100%) and renal (46%) lupus. In contrast to BALB/c, Bl/6-PIL mice did not develop any signs of arthritis. CONCLUSION: PIL in BALB/c mice is characterized by severe organ involvement, typical autoabs and by a mild-erosive arthritis with similarities to, but also with distinct differences from, RA. PIL may help to study arthritis along with other key features of systemic lupus erythematosus after therapeutic interventions or in knock-out models based on a BALB/c but not on a C57BL/6 background.
Asunto(s)
Artritis Experimental/fisiopatología , Artritis Reumatoide/fisiopatología , Autoanticuerpos/sangre , Lupus Eritematoso Sistémico/complicaciones , Animales , Artritis Experimental/etiología , Artritis Reumatoide/etiología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Granulocitos/metabolismo , Inflamación/etiología , Inflamación/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Índice de Severidad de la Enfermedad , Especificidad de la Especie , Terpenos/toxicidad , Factores de TiempoRESUMEN
OBJECTIVE: The binding of abatacept (CTLA-4Ig) to the B7 ligands CD80 and CD86 prevents the engagement of CD28 on T cells and thereby prevents effector T cell activation. In addition, a direct effect of CTLA-4Ig on antigen-presenting cells (APCs) could contribute to the therapeutic effect. To further elucidate the mechanism of CTLA-4Ig, we performed phenotype and functional analyses of APCs in patients with rheumatoid arthritis (RA) before and after the initiation of CTLA-4Ig therapy. METHODS: Peripheral blood mononuclear cells were analyzed before and at 2 and 4 weeks after the initiation of CTLA-4Ig therapy. Proportions of APCs were determined by flow cytometry. CD14+ monocytes were further analyzed for the expression of costimulatory and adhesion molecules and for their transendothelial migratory capacity in vitro. In addition, CD14+ monocytes from healthy controls were analyzed for their migratory and spreading capacity. RESULTS: Proportions and absolute numbers of monocytes were significantly increased in RA patients treated with CTLA-4Ig. The expression of several adhesion molecules was significantly diminished. In addition, monocytes displayed a significant reduction in their endothelial adhesion and transendothelial migratory capacity upon treatment with CTLA-4Ig. Likewise, isolated monocytes from healthy controls revealed a significant reduction in their migratory and spreading activity after preincubation with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. CONCLUSION: We describe direct effects of CTLA-4Ig therapy on phenotype and functional characteristics of monocytes in RA patients that might interfere with the migration of monocytes to the synovial tissue. This additional mechanism of CTLA-4Ig might contribute to the beneficial effects of CTLA-4Ig treatment in RA patients.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Movimiento Celular/efectos de los fármacos , Inmunoconjugados/uso terapéutico , Monocitos/efectos de los fármacos , Monocitos/patología , Abatacept , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/patología , Antirreumáticos/uso terapéutico , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Moléculas de Adhesión Celular/metabolismo , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Receptores de Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/metabolismoRESUMEN
SIN 1, the bioactive metabolite of molsidomine, not only appears to lack the problem of inducing nitrate tolerance, but also exerts antiaggregatory and fibrinolytic properties. These effects, which either are not or only in part shared by the drug isosorbide-5-mononitrate, might be beneficial in the prevention of thromboembolic complications in cardiovascular disease. In contrast to the effects of acetylsalicylic acid, SIN 1 already inhibits aggregation during the first phase of aggregation, and it inhibits aggregations induced by agonists that are not or only marginally influenced by acetylsalicylic acid (such as the aggregation induced by platelet activating factor). Thus, the antiaggregatory effects of molsidomine cannot replace the effects of acetylsalicylic acid, while a combination of both drugs might be of benefit in the treatment of patients with cardiovascular disease.