Dataset Information

Inflammation in sickle cell disease.

ABSTRACT: The primary ?-globin gene mutation that causes sickle cell disease (SCD) has significant pathophysiological consequences that result in hemolytic events and the induction of the inflammatory processes that ultimately lead to vaso-occlusion. In addition to their role in the initiation of the acute painful vaso-occlusive episodes that are characteristic of SCD, inflammatory processes are also key components of many of the complications of the disease including autosplenectomy, acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy and stroke. We, herein, discuss the events that trigger inflammation in the disease, as well as the mechanisms, inflammatory molecules and cells that propagate these inflammatory processes. Given the central role that inflammation plays in SCD pathophysiology, many of the therapeutic approaches currently under pre-clinical and clinical development for the treatment of SCD endeavor to counter aspects or specific molecules of these inflammatory processes and it is possible that, in the future, we will see anti-inflammatory drugs being used either together with, or in place of, hydroxyurea in those SCD patients for whom hematopoietic stem cell transplants and evolving gene therapies are not a viable option.

SUBMITTER: Conran N

PROVIDER: S-EPMC6314308 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inflammation in sickle cell disease.

Conran Nicola N Belcher John D JD

Clinical hemorheology and microcirculation 20180101 2-3

The primary β-globin gene mutation that causes sickle cell disease (SCD) has significant pathophysiological consequences that result in hemolytic events and the induction of the inflammatory processes that ultimately lead to vaso-occlusion. In addition to their role in the initiation of the acute painful vaso-occlusive episodes that are characteristic of SCD, inflammatory processes are also key components of many of the complications of the disease including autosplenectomy, acute chest syndrome ...[more]

PMID: 29614637

Similar Datasets

Project description:Rationale: Asthma is a common comorbid condition in sickle cell disease (SCD). However, obstructive lung disease is prevalent in SCD, independent of a diagnosis of asthma. It is speculated that the heightened state of inflammation in SCD, involving pathways distinct from allergic asthma, may underlie the SCD-specific obstructive disease. Objective: The objective of the study was to compare airway and systemic inflammatory markers between SCD patients with pulmonary manifestations and patients with allergic asthma, and correlate the discriminating inflammatory markers with clinical measures of pulmonary disease. Materials and Methods: In a pilot translational study conducted at the Children's Hospital at Montefiore, 15 patients with SCD, and history of asthma, airway obstruction, or airway hyper-reactivity, and 15 control patients with allergic asthma 6-21 years of age were recruited. Inflammatory markers, including peripheral blood T helper cell subsets, serum and exhaled breath condensate (EBC) cytokines and chemokines of the Th-1/Th-17, Th-2, and monocytic pathways, and serum cysteinyl leukotrienes B4 (LTB4), were quantified, compared between the study groups, and correlated with atopic sensitization, pulmonary function tests, and markers of hemolysis. Results: White blood cells (P?<?0.05) and monocytes (P?<?0.001) were elevated in the SCD group, while atopic characteristics were higher in the control asthma group. Tumor necrosis factor-alpha (P?<?0.01), interferon gamma inducible protein (IP)-10 (P?<?0.05), and interleukin-4 (P?<?0.01) in serum and monocyte chemotactic protein (MCP)-1 in EBC were higher in the SCD group (P???0.05). Forced vital capacity (FVC) and forced expiratory volume in 1?s (FEV1) in patients with SCD inversely correlated with serum IP-10 and LTB4 levels. Conclusions: Compared with atopic asthmatic patients, inflammatory markers involving Th-1, Th-2, and monocytic pathways were higher in the SCD group, among which Th-1 measures correlated with pulmonary function deficits.

Project description:Sickle cell disease (SCD) is a genetic disease caused by a single mutation in the ?-globin gene, leading to the production of an abnormal hemoglobin called hemoglobin S (HbS), which polymerizes under deoxygenation, and induces the sickling of red blood cells (RBCs). Sickled RBCs are very fragile and rigid, and patients consequently become anemic and develop frequent and recurrent vaso-occlusive crises. However, it is now evident that SCD is not only a RBC rheological disease. Accumulating evidence shows that SCD is also characterized by the presence of chronic inflammation and oxidative stress, participating in the development of chronic vasculopathy and several chronic complications. The accumulation of hemoglobin and heme in the plasma, as a consequence of enhanced intravascular hemolysis, decreases nitric oxide bioavailability and enhances the production of reactive oxygen species (ROS). Heme and hemoglobin also represent erythrocytic danger-associated molecular pattern molecules (eDAMPs), which may activate endothelial inflammation through TLR-4 signaling and promote the development of complications, such as acute chest syndrome. It is also suspected that heme may activate the innate immune complement system and stimulate neutrophils to release neutrophil extracellular traps. A large amount of microparticles (MPs) from various cellular origins (platelets, RBCs, white blood cells, endothelial cells) is also released into the plasma of SCD patients and participate in the inflammation and oxidative stress in SCD. In turn, this pro-inflammatory and oxidative stress environment further alters the RBC properties. Increased pro-inflammatory cytokine concentrations promote the activation of RBC NADPH oxidase and, thus, raise the production of intra-erythrocyte ROS. Such enhanced oxidative stress causes deleterious damage to the RBC membrane and further alters the deformability of the cells, modifying their aggregation properties. These RBC rheological alterations have been shown to be associated to specific SCD complications, such as leg ulcers, priapism, and glomerulopathy. Moreover, RBCs positive for the Duffy antigen receptor for chemokines may be very sensitive to various inflammatory molecules that promote RBC dehydration and increase RBC adhesiveness to the vascular wall. In summary, SCD is characterized by a vicious circle between abnormal RBC rheology and inflammation, which modulates the clinical severity of patients.

Dataset Information

Inflammation in sickle cell disease.

Publications

Inflammation in sickle cell disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets