Hyperleukocytosis is a complication of various leukemias and can result in life-threatening leukostasis. Critical white blood cell (WBC) counts are conventionally defined as higher than 100 × 109/l in acute myeloid leukemia and > 300 × 109/l in acute lymphatic leukemia and other leukemic disorders (e. g. chronic myeloid leukemia). Leukocytapheresis is a therapeutic tool to reduce leukocyte counts in patients with symptomatic or threatening leukostasis until induction chemotherapy works. In patients with temporary contraindications against cytotoxic drugs, e.g. during pregnancy, leukocytapheresis can be used as a bridging therapy until conventional chemotherapy can be started. Therapeutic leukocytapheresis should be performed in specialized centers by experienced, well-trained staff. Thorough monitoring of the patients is extremely relevant. During a single procedure, WBC count can be reduced by 10–70%. Treatment should be repeated daily and can be discontinued when the symptoms of leukostasis have been resolved and/or leukocyte counts have fallen below the critical thresholds. There are no prospective studies evaluating the clinical efficacy of therapeutic leukocytapheresis in patients with hyperleukocytosis. It can be concluded from retrospective studies that leukocytapheresis might have some beneficial effect in early morbidity and mortality of patients with newly diagnosed AML but has no influence on overall long-term survival. Induction chemotherapy is the most important treatment in these patients and must never be postponed. / Leukozytose ist eine Komplikation verschiedener Leukämien und kann zur lebensbedrohlichen Leukostase führen. Als kritische Leukozytenzahlen gelten im Allgemeinen Werte über 100 × 109/l bei akuten myeloischen Leukämien und über 300 × 109/l bei akuter lymphatischer Leukämie und anderen Leukämieformen (z. B. chronisch-myeloische Leukämie). Mittels therapeutischer Leuko zytapherese können pathologisch erhöhte Leukozytenwerte bei Patienten mit symptomatischer oder drohender Leukostase reduziert werden, bis die Wirkung der Induktions-Chemotherapie einsetzt. Bei Patienten mit vorübergehenden Kontraindikationen gegen Zytostatika, wie z.B. in der Schwangerschaft, dient die Leukozytapherese zur Überbrückung des Zeitraums, bis die konventionelle Chemotherapie begonnen werden kann. Leukozytapheresen sollten nur in spezialisierten Zentren von erfahrenem, geschultem Personal durchgeführt werden. Eine sorgfältige Überwachung der Patienten ist von besonderer Bedeutung. Während einer Behandlung kann die Leukozytenzahl um 10–70% reduziert werden. Die Behandlung sollte täglich wiederholt werden, bis die Leukostasesymptomatik abgeklungen bzw. die Leukozytenzahl unter die kritische Interventionsschwelle abgefallen ist. Es mangelt an prospektiven, randomisierten, kontrollierten Studien, die den klinischen Effekt der therapeutischen Leukozytapherese bei Patienten mit Leukostase evaluieren. Retrospektive Studien lassen auf eine therapeutische Wirksamkeit der Leukozytapherese hinsichtlich Frühmorbidität und –mortalität bei Patienten mit neu diagnostizierter AML schließen. Ein Einfluss dieser Therapie auf das Gesamtüberleben von AML-Patienten konnte nicht nachgewiesen werden. Die entscheidende Therapie für diese Patienten ist die Induktions-Chemotherapie, die deshalb auch keinesfalls verzögert werden sollte. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Abnormal leukocyte adhesion (i.e. leukostasis) to retinal vascular endothelial cells occurs in early diabetes. The processes of leukostasis have been clearly demonstrated in the vascular endothelium of patients with diabetes. In non-proliferative DR, clinical outcomes are manifested by excessive permeability from inflammatory progression leading to inner blood retinal barrier disruption, endothelial cell damage and widespread capillary nonperfusion. Diabetes promotes vascular leakage in DR by upregulation of adhesion molecules. Moreover, many of the pathological changes in NPDR are related to abnormalities in retinal blood flow. Studies have shown that specific circulating markers of inflammatory activity and endothelial dysfunction are associated with clinical signs of diabetic retinopathy. However, few have found an association between circulating levels of inflammatory and endothelial dysfunctional markers and abnormal retinal hemodynamics in patients with non-proliferative DR. The specific aims of this thesis are as follows: (Chapter 3)To correlate baseline levels of inflammatory and endothelial dysfunction markers and 1) baseline retinal arteriolar hemodynamics and 2) any disturbance in retinal hemodynamics over 6-month time in terms of vessel diameter, blood velocity, maximum-to-minimum velocity ratio and volumetric flow. In Chapter 4: To correlate circulating levels of inflammatory and endothelial dysfunction markers and 1) baseline vascular reactivity and 2) any disturbance in vascular reactivity after 6-month time in terms of vessel diameter, blood velocity, maximum-to-minimum velocity ratio and volumetric flow in patients with increasing non-proliferative diabetic retinopathy (NPDR) severity. Methods for Chapter 3: Diabetes subjects were stratified into either mild-to-moderate (Group 2) or moderate-to-severe (Group 3) NPDR based on their retinopathy status. Age-matched non-diabetics were recruited as controls (Group 1). Forearm blood sample was collected to determine baseline levels of inflammatory and endothelial dysfunctional markers. At visit 1, baseline retinal hemodynamics was acquired using Canon Laser Blood Flowmeter. Patients returned for a visit 2 (6 month follow-up visit) and retinal hemodynamics was reassessed. Baseline levels of inflammatory and endothelial dysfunctional markers compared between groups and correlated with both baseline and change in retinal hemodynamic parameters over 6-month time. For Chapter 4: Diabetes subjects were stratified into either mild-to-moderate NPDR or moderate-to-severe NPDR based on their retinopathy status. Age-matched non-diabetics were recruited as controls. At visit 1, forearm blood sample was collected to determine levels of inflammatory and endothelial dysfunctional markers and baseline vascular reactivity response was acquired. Retinal blood flow data was acquired while subjects breathed air. Retinal blood flow measurements were then acquired after exposure to isocapnic hyperoxic stimuli. At visit 2 (6 month follow-up), retinal vascular reactivity was reassessed. Baseline levels of inflammatory and endothelial dysfunctional markers compared between groups and correlated with both magnitude of baseline and change in vascular reactivity in terms of retinal hemodynamics. Results of Chapter 3: Maximum-to-minimum velocity ratio (max: min) was found to be significantly elevated in the group 3 compared to group 1 at baseline (0.72 vs. 0.49, after Bonferroni correction P<0.01). Both sICAM-1 and sE-selectin were significantly elevated as a function of group (ANOVA p=0.02 and p=0.04). A post hoc Bonferroni test showed that Group 3 had significantly higher in both sICAM-1 and sE-selectin levels compared to Group 1 (234.0 vs. 151.5 ng/ml, P=0.02 and 53.4 vs. 27.6 ng/ml, P<0.01, respectively). Hemoglobin A1c was significantly elevated across the groups (ANOVA p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher hemoglobin A1c level compared to Group 1 (7.9 vs. 5.6 % , P<0.01). There were no significant associations found between baseline markers of inflammation and baseline retinal hemodynamics across all groups. The Δ velocity was correlated with the baseline sICAM-1 (r=0.42, p=0.02) and A1c levels (r=0.37, p=0.04) in patients with NPDR. After adjustment for all other variables (A1c, hsCRP and vWF), Δ velocity, sICAM-1 and A1c were found not to be reliable predictors of baseline retinal hemodynamics. For Chapter 4: There were no significant differences in magnitude of retinal vascular reactivity in hemodynamic parameters between groups at visit 1 or visit 2. Over 6 months time, compliance was found to be significantly reduced in patients of Group 3 compared to Group 2 (-0.4 vs. 0.1, t-test p<0.01). Both sICAM-1 and sE-selectin were significantly elevated as a function of group (ANOVA p=0.02 and p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher in both sICAM-1 and sE-selectin levels compared to Group 1 (243.4 vs. 157.3ngml, P<0.01 and 57.0 vs. 29.3 ng/ml, P<0.01, respectively). Hemoglobin A1c was significantly elevated across the groups (ANOVA p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher hemoglobin A1c level compared to Group 1 (8.8 vs. 5.6 % , P<0.01). Baseline VR in blood velocity weakly correlates with sE-selectin (r=0.31, p=0.04) across all groups while sVCAM-1 was associated with VR in terms of blood flow (r=-0.62, p<0.01) in patients with mild-to-moderate NPDR. The ∆ blood flow after 6 months was found to be weakly associated with sE-selectin (r=0.46, p=0.03) across all groups. Finally, the ∆ blood velocity after 6 month time was found to be moderately correlated with baseline vWF Ag level (r=-0.78, p=0.02). Multiple regression analysis found that vascular inflammatory and endothelial function markers had weak predictive power for Δ hemodynamic parameters. Conclusions Chapter 3: We found weak associations between circulating markers and baseline or the disturbance in retinal hemodynamics after 6 months time. Overall, we found both an increase in rigidity of the arteriolar circulation and elevated inflammatory adhesion markers (sICAM-1 and sE-selectin) within the same population sample. Change in velocity over the follow-up period was correlated with sICAM-1 and A1c levels in patients with NPDR but the level of association was such that neither sICAM-1 nor A1c proved to reliably predict retinal hemodynamics. Finally, in Chapter 4 we demonstrated two important characteristics in early NPDR; 1) a disturbance in vascular reactivity in terms of compliance and 2) an increase in systemic markers of inflammation were found in patients with NPDR. Although systemic markers of vascular inflammation and endothelial dysfunction are not predictive of hemodynamic parameters, our study found moderate associations between baseline and disturbances in VR after 6 months time. Therefore, there is evidence that inflammation and vascular function may be related with respect to their development in NPDR.

Abnormal leukocyte adhesion (i.e. leukostasis) to retinal vascular endothelial cells occurs in early diabetes. The processes of leukostasis have been clearly demonstrated in the vascular endothelium of patients with diabetes. In non-proliferative DR, clinical outcomes are manifested by excessive permeability from inflammatory progression leading to inner blood retinal barrier disruption, endothelial cell damage and widespread capillary nonperfusion. Diabetes promotes vascular leakage in DR by upregulation of adhesion molecules. Moreover, many of the pathological changes in NPDR are related to abnormalities in retinal blood flow. Studies have shown that specific circulating markers of inflammatory activity and endothelial dysfunction are associated with clinical signs of diabetic retinopathy. However, few have found an association between circulating levels of inflammatory and endothelial dysfunctional markers and abnormal retinal hemodynamics in patients with non-proliferative DR. The specific aims of this thesis are as follows: (Chapter 3)To correlate baseline levels of inflammatory and endothelial dysfunction markers and 1) baseline retinal arteriolar hemodynamics and 2) any disturbance in retinal hemodynamics over 6-month time in terms of vessel diameter, blood velocity, maximum-to-minimum velocity ratio and volumetric flow. In Chapter 4: To correlate circulating levels of inflammatory and endothelial dysfunction markers and 1) baseline vascular reactivity and 2) any disturbance in vascular reactivity after 6-month time in terms of vessel diameter, blood velocity, maximum-to-minimum velocity ratio and volumetric flow in patients with increasing non-proliferative diabetic retinopathy (NPDR) severity. Methods for Chapter 3: Diabetes subjects were stratified into either mild-to-moderate (Group 2) or moderate-to-severe (Group 3) NPDR based on their retinopathy status. Age-matched non-diabetics were recruited as controls (Group 1). Forearm blood sample was collected to determine baseline levels of inflammatory and endothelial dysfunctional markers. At visit 1, baseline retinal hemodynamics was acquired using Canon Laser Blood Flowmeter. Patients returned for a visit 2 (6 month follow-up visit) and retinal hemodynamics was reassessed. Baseline levels of inflammatory and endothelial dysfunctional markers compared between groups and correlated with both baseline and change in retinal hemodynamic parameters over 6-month time. For Chapter 4: Diabetes subjects were stratified into either mild-to-moderate NPDR or moderate-to-severe NPDR based on their retinopathy status. Age-matched non-diabetics were recruited as controls. At visit 1, forearm blood sample was collected to determine levels of inflammatory and endothelial dysfunctional markers and baseline vascular reactivity response was acquired. Retinal blood flow data was acquired while subjects breathed air. Retinal blood flow measurements were then acquired after exposure to isocapnic hyperoxic stimuli. At visit 2 (6 month follow-up), retinal vascular reactivity was reassessed. Baseline levels of inflammatory and endothelial dysfunctional markers compared between groups and correlated with both magnitude of baseline and change in vascular reactivity in terms of retinal hemodynamics. Results of Chapter 3: Maximum-to-minimum velocity ratio (max: min) was found to be significantly elevated in the group 3 compared to group 1 at baseline (0.72 vs. 0.49, after Bonferroni correction P<0.01). Both sICAM-1 and sE-selectin were significantly elevated as a function of group (ANOVA p=0.02 and p=0.04). A post hoc Bonferroni test showed that Group 3 had significantly higher in both sICAM-1 and sE-selectin levels compared to Group 1 (234.0 vs. 151.5 ng/ml, P=0.02 and 53.4 vs. 27.6 ng/ml, P<0.01, respectively). Hemoglobin A1c was significantly elevated across the groups (ANOVA p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher hemoglobin A1c level compared to Group 1 (7.9 vs. 5.6 % , P<0.01). There were no significant associations found between baseline markers of inflammation and baseline retinal hemodynamics across all groups. The Δ velocity was correlated with the baseline sICAM-1 (r=0.42, p=0.02) and A1c levels (r=0.37, p=0.04) in patients with NPDR. After adjustment for all other variables (A1c, hsCRP and vWF), Δ velocity, sICAM-1 and A1c were found not to be reliable predictors of baseline retinal hemodynamics. For Chapter 4: There were no significant differences in magnitude of retinal vascular reactivity in hemodynamic parameters between groups at visit 1 or visit 2. Over 6 months time, compliance was found to be significantly reduced in patients of Group 3 compared to Group 2 (-0.4 vs. 0.1, t-test p<0.01). Both sICAM-1 and sE-selectin were significantly elevated as a function of group (ANOVA p=0.02 and p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher in both sICAM-1 and sE-selectin levels compared to Group 1 (243.4 vs. 157.3ngml, P<0.01 and 57.0 vs. 29.3 ng/ml, P<0.01, respectively). Hemoglobin A1c was significantly elevated across the groups (ANOVA p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher hemoglobin A1c level compared to Group 1 (8.8 vs. 5.6 % , P<0.01). Baseline VR in blood velocity weakly correlates with sE-selectin (r=0.31, p=0.04) across all groups while sVCAM-1 was associated with VR in terms of blood flow (r=-0.62, p<0.01) in patients with mild-to-moderate NPDR. The ∆ blood flow after 6 months was found to be weakly associated with sE-selectin (r=0.46, p=0.03) across all groups. Finally, the ∆ blood velocity after 6 month time was found to be moderately correlated with baseline vWF Ag level (r=-0.78, p=0.02). Multiple regression analysis found that vascular inflammatory and endothelial function markers had weak predictive power for Δ hemodynamic parameters. Conclusions Chapter 3: We found weak associations between circulating markers and baseline or the disturbance in retinal hemodynamics after 6 months time. Overall, we found both an increase in rigidity of the arteriolar circulation and elevated inflammatory adhesion markers (sICAM-1 and sE-selectin) within the same population sample. Change in velocity over the follow-up period was correlated with sICAM-1 and A1c levels in patients with NPDR but the level of association was such that neither sICAM-1 nor A1c proved to reliably predict retinal hemodynamics. Finally, in Chapter 4 we demonstrated two important characteristics in early NPDR; 1) a disturbance in vascular reactivity in terms of compliance and 2) an increase in systemic markers of inflammation were found in patients with NPDR. Although systemic markers of vascular inflammation and endothelial dysfunction are not predictive of hemodynamic parameters, our study found moderate associations between baseline and disturbances in VR after 6 months time. Therefore, there is evidence that inflammation and vascular function may be related with respect to their development in NPDR.

Hyperleukocytosis is a complication of various leukemias and can result in life-threatening leukostasis. Critical white blood cell (WBC) counts are conventionally defined as higher than 100 × 109/l in acute myeloid leukemia and > 300 × 109/l in acute lymphatic leukemia and other leukemic disorders (e. g. chronic myeloid leukemia). Leukocytapheresis is a therapeutic tool to reduce leukocyte counts in patients with symptomatic or threatening leukostasis until induction chemotherapy works. In patients with temporary contraindications against cytotoxic drugs, e.g. during pregnancy, leukocytapheresis can be used as a bridging therapy until conventional chemotherapy can be started. Therapeutic leukocytapheresis should be performed in specialized centers by experienced, well-trained staff. Thorough monitoring of the patients is extremely relevant. During a single procedure, WBC count can be reduced by 10–70%. Treatment should be repeated daily and can be discontinued when the symptoms of leukostasis have been resolved and/or leukocyte counts have fallen below the critical thresholds. There are no prospective studies evaluating the clinical efficacy of therapeutic leukocytapheresis in patients with hyperleukocytosis. It can be concluded from retrospective studies that leukocytapheresis might have some beneficial effect in early morbidity and mortality of patients with newly diagnosed AML but has no influence on overall long-term survival. Induction chemotherapy is the most important treatment in these patients and must never be postponed. / Leukozytose ist eine Komplikation verschiedener Leukämien und kann zur lebensbedrohlichen Leukostase führen. Als kritische Leukozytenzahlen gelten im Allgemeinen Werte über 100 × 109/l bei akuten myeloischen Leukämien und über 300 × 109/l bei akuter lymphatischer Leukämie und anderen Leukämieformen (z. B. chronisch-myeloische Leukämie). Mittels therapeutischer Leuko zytapherese können pathologisch erhöhte Leukozytenwerte bei Patienten mit symptomatischer oder drohender Leukostase reduziert werden, bis die Wirkung der Induktions-Chemotherapie einsetzt. Bei Patienten mit vorübergehenden Kontraindikationen gegen Zytostatika, wie z.B. in der Schwangerschaft, dient die Leukozytapherese zur Überbrückung des Zeitraums, bis die konventionelle Chemotherapie begonnen werden kann. Leukozytapheresen sollten nur in spezialisierten Zentren von erfahrenem, geschultem Personal durchgeführt werden. Eine sorgfältige Überwachung der Patienten ist von besonderer Bedeutung. Während einer Behandlung kann die Leukozytenzahl um 10–70% reduziert werden. Die Behandlung sollte täglich wiederholt werden, bis die Leukostasesymptomatik abgeklungen bzw. die Leukozytenzahl unter die kritische Interventionsschwelle abgefallen ist. Es mangelt an prospektiven, randomisierten, kontrollierten Studien, die den klinischen Effekt der therapeutischen Leukozytapherese bei Patienten mit Leukostase evaluieren. Retrospektive Studien lassen auf eine therapeutische Wirksamkeit der Leukozytapherese hinsichtlich Frühmorbidität und –mortalität bei Patienten mit neu diagnostizierter AML schließen. Ein Einfluss dieser Therapie auf das Gesamtüberleben von AML-Patienten konnte nicht nachgewiesen werden. Die entscheidende Therapie für diese Patienten ist die Induktions-Chemotherapie, die deshalb auch keinesfalls verzögert werden sollte. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

La rétinopathie diabétique est associée à plusieurs changements pathologiques du lit vasculaire rétinien, incluant l’ouverture de la barrière hémato-rétinienne, l’inflammation vasculaire et la modification du débit sanguin. Récemment, il a été proposé que le récepteur B1 des kinines, qui est surexprimé dans la rétine diabétique, puisse être impliqué dans le développement de ces altérations vasculaires. Ainsi, cette thèse présente les effets de traitements pharmacologiques avec des antagonistes du récepteur B1 sur la perfusion rétinienne, la perméabilité vasculaire, l’infiltration des leucocytes (leucostasie), l’expression de médiateurs de l’inflammation et la production d’anion superoxyde dans la rétine du rat rendu diabétique avec la streptozotocine (STZ). Les résultats obtenus montrent que l’application oculaire (10 µl d’une solution à 1%, deux fois par jour pendant 7 jours) de LF22-0542, un antagoniste hydrosoluble du récepteur B1, bloque significativement l’hyperperméabilité vasculaire, la leucostasie, le stress oxydatif et l’expression génique de médiateurs de l’inflammation (B1R, iNOS, COX-2, VEGF-R2, IL-1β et HIF-1α) dans la rétine chez le rat à 2 semaines de diabète. L’administration orale (3 mg/kg) d’un antagoniste non-peptidique et sélectif pour le récepteur B1, le SSR240612, entraîne une diminution du débit sanguin rétinien 4 jours après l’induction du diabète mais n’a aucun effet sur la réduction de la perfusion rétinienne à 6 semaines. Le récepteur B1 joue donc un rôle protecteur au tout début du diabète en assurant le maintien d’un débit sanguin normal dans la rétine; un effet qui n’est toutefois pas maintenu pendant la progression du diabète. Ces données présentent ainsi la dualité du récepteur B1 avec des effets à la fois protecteurs et délétères. Elles suggèrent aussi un rôle important pour le récepteur B1 dans l’inflammation rétinienne et le développement des altérations vasculaires. Le récepteur B1 pourrait donc représenter une nouvelle cible thérapeutique pour le traitement de la rétinopathie diabétique. / Diabetic retinopathy is associated with retinal vascular changes, including blood retinal barrier breakdown, vascular inflammation and blood flow alterations. It has been proposed that kinin B1 receptor, which is upregulated in the diabetic retina, could be involved in the development of these pathological features of diabetic retinopathy. In a rat model of diabetes induced by Streptozotocin (STZ), the effects of kinin B1 receptor antagonists on retinal perfusion, vascular permeability, leukostasis, gene expression of inflammatory mediators and production of superoxide anion in the retina were evaluated. The results show that in 2-week diabetic rats, topical ocular application of the water soluble kinin B1 receptor antagonist LF22-0542 (10 µl of 1% solution, twice per day) for a 7-day period reverses vascular hyperpermeability, leukostasis, oxidative stress and gene expression of inflammatory mediators (B1R, iNOS, COX-2, VEGF-R2, IL-1β and HIF-1α) in the retina. Single oral administration (3 mg/kg) of SSR240612, a selective non-peptide B1 receptor antagonist, induces a decrease of retinal blood flow in 4-day diabetic rats but has no effect on retinal blood flow reduction present at 6 weeks of diabetes. Therefore, B1 receptor has a protective role in early diabetes by preserving a normal blood flow in the retina. These data suggest that B1 receptor exerts protective and adverse effects in the diabetic retina. They also support a key role for B1 receptor in retinal inflammation and the development of vascular alterations. B1 receptor could therefore represent a promising therapeutic target for the treatment of diabetic retinopathy.

La rétinopathie diabétique est associée à plusieurs changements pathologiques du lit vasculaire rétinien, incluant l’ouverture de la barrière hémato-rétinienne, l’inflammation vasculaire et la modification du débit sanguin. Récemment, il a été proposé que le récepteur B1 des kinines, qui est surexprimé dans la rétine diabétique, puisse être impliqué dans le développement de ces altérations vasculaires. Ainsi, cette thèse présente les effets de traitements pharmacologiques avec des antagonistes du récepteur B1 sur la perfusion rétinienne, la perméabilité vasculaire, l’infiltration des leucocytes (leucostasie), l’expression de médiateurs de l’inflammation et la production d’anion superoxyde dans la rétine du rat rendu diabétique avec la streptozotocine (STZ). Les résultats obtenus montrent que l’application oculaire (10 µl d’une solution à 1%, deux fois par jour pendant 7 jours) de LF22-0542, un antagoniste hydrosoluble du récepteur B1, bloque significativement l’hyperperméabilité vasculaire, la leucostasie, le stress oxydatif et l’expression génique de médiateurs de l’inflammation (B1R, iNOS, COX-2, VEGF-R2, IL-1β et HIF-1α) dans la rétine chez le rat à 2 semaines de diabète. L’administration orale (3 mg/kg) d’un antagoniste non-peptidique et sélectif pour le récepteur B1, le SSR240612, entraîne une diminution du débit sanguin rétinien 4 jours après l’induction du diabète mais n’a aucun effet sur la réduction de la perfusion rétinienne à 6 semaines. Le récepteur B1 joue donc un rôle protecteur au tout début du diabète en assurant le maintien d’un débit sanguin normal dans la rétine; un effet qui n’est toutefois pas maintenu pendant la progression du diabète. Ces données présentent ainsi la dualité du récepteur B1 avec des effets à la fois protecteurs et délétères. Elles suggèrent aussi un rôle important pour le récepteur B1 dans l’inflammation rétinienne et le développement des altérations vasculaires. Le récepteur B1 pourrait donc représenter une nouvelle cible thérapeutique pour le traitement de la rétinopathie diabétique. / Diabetic retinopathy is associated with retinal vascular changes, including blood retinal barrier breakdown, vascular inflammation and blood flow alterations. It has been proposed that kinin B1 receptor, which is upregulated in the diabetic retina, could be involved in the development of these pathological features of diabetic retinopathy. In a rat model of diabetes induced by Streptozotocin (STZ), the effects of kinin B1 receptor antagonists on retinal perfusion, vascular permeability, leukostasis, gene expression of inflammatory mediators and production of superoxide anion in the retina were evaluated. The results show that in 2-week diabetic rats, topical ocular application of the water soluble kinin B1 receptor antagonist LF22-0542 (10 µl of 1% solution, twice per day) for a 7-day period reverses vascular hyperpermeability, leukostasis, oxidative stress and gene expression of inflammatory mediators (B1R, iNOS, COX-2, VEGF-R2, IL-1β and HIF-1α) in the retina. Single oral administration (3 mg/kg) of SSR240612, a selective non-peptide B1 receptor antagonist, induces a decrease of retinal blood flow in 4-day diabetic rats but has no effect on retinal blood flow reduction present at 6 weeks of diabetes. Therefore, B1 receptor has a protective role in early diabetes by preserving a normal blood flow in the retina. These data suggest that B1 receptor exerts protective and adverse effects in the diabetic retina. They also support a key role for B1 receptor in retinal inflammation and the development of vascular alterations. B1 receptor could therefore represent a promising therapeutic target for the treatment of diabetic retinopathy.