The role of nitric oxide in arthritic joints: a therapeutic target?

Nitric oxide (NO) is produced by many cell types in the joint, and its expression is delicately regulated. Depending on its concentration and cellular origin, NO appears to have both pro- and anti-inflammatory potential in the joint. Constitutively expressed nitric oxide synthase (NOS) produces small amounts of NO, which is essential for normal physiological homeostasis. However, inflammatory stimuli such as endotoxins, cytokines, and growth factors promote inducible NOS (iNOS) expression, initially as an anti-inflammatory response, and catalyse a high output of NO. Excessive NO can amplify inflammatory pathways and contribute to the development and maintenance of arthritis. Consequently, proper regulation of NO synthesis can lead to a novel therapeutic approach for inflammatory joint diseases. Further careful study will be necessary to develop new drugs to regulate the NO pathway and to determine the dosage, timing of administration, and duration of treatment in order to avoid both undesirable immunostimulatory effects and immunosuppressive effects. Received: February 18, 2000     

The role of insulin resistance in nonalcoholic steatohepatitis and liver disease development – a potential therapeutic target?

Insulin resistance (IR) is defined by the inability of insulin to exert its metabolic actions, due to impaired activation of intracellular insulin signaling. This condition is caused by genetic defects or by environmental conditions, among which the most common is obesity. Systemic IR determines the development of hepatic fat accumulation, which can progress to nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma, and is a major determinant of liver disease independently of coexisting factors. Therefore, insulin-sensitizing drugs are currently under evaluation to improve steatohepatitis. Indeed, manipulation of nuclear hormone receptors is already under scrutiny for liver disease prevention by amelioration of IR, whereas NOTCH signaling inhibition represents a novel approach. Nevertheless, further research is warranted to better understand the mechanism linking IR to progressive fibrogenesis in the absence of inflammation and to identify novel drug targets.     

The vascular endothelium in diabetes—a therapeutic target?

Insulin resistance affects the vascular endothelium, and contributes to systemic insulin resistance by directly impairing the actions of insulin to redistribute blood flow as part of its normal actions driving muscle glucose uptake. Impaired vascular function is a component of the insulin resistance syndrome, and is a feature of type 2 diabetes. On this basis, the vascular endothelium has emerged as a therapeutic target where the intent is to improve systemic metabolic state by improving vascular function. We review the available literature presenting studies in humans, evaluating the effects of metabolically targeted and vascular targeted therapies on insulin action and systemic metabolism. Therapies that improve systemic insulin resistance exert strong concurrent effects to improve vascular function and vascular insulin action. RAS-acting agents and statins have widely recognized beneficial effects on vascular function but have not uniformly produced the hoped-for metabolic benefits. These observations support the notion that systemic metabolic benefits can arise from therapies targeted at the endothelium, but improving vascular insulin action does not result from all treatments that improve endothelium-dependent vasodilation. A better understanding of the mechanisms of insulin’s actions in the vascular wall will advance our understanding of the specificity of these responses, and allow us to better target the vasculature for metabolic benefits.     

Airway dehydration: a therapeutic target in asthma?

BACKGROUND: Airway dehydration triggers exercise-induced bronchoconstriction in virtually all patients with active asthma. We are not aware of any investigations of airway dehydration in patients with naturally occurring asthma exacerbations. We wish to investigate whether airway dehydration occurs in acute asthmatic patients in the emergency department, and its functional significance. METHODS: In a pilot study on 10 asthmatic patients and 10 control subjects in the emergency department, respiratory rate was counted manually, and relative humidity of expired air was recorded using an air probe hygrometer. In parallel laboratory studies carried out over 2 consecutive days, 19 asthmatics and 10 control subjects were challenged initially with dry air, and on the second day with humidified air. FEV(1) and humidity measurements were made immediately before and after the tachypnea challenges. RESULTS: In the emergency department, the asthmatic group was more tachypneic (p < 0.0001) and their expired air was drier (p < 0.0001) than the control group. Following a dry-air tachypnea challenge in the laboratory, which caused dehydration of the expired air in all subjects, half of the asthmatics, but none of the control subjects, demonstrated a fall of > 10% in FEV(1) from baseline. This bronchoconstriction was prevented by humidifying the inspired air; tachypnea with no water loss did not affect lung function in asthmatic subjects. CONCLUSIONS: Dehydration of the expired air is present in asthmatic patients in the emergency department. The bronchoconstriction triggered by dry-air tachypnea challenge in the laboratory can be prevented by humidifying the inspired air. Airway rehydration merits further investigation as a potential adjunct to acute treatment of asthma exacerbations.     

Angiogenesis in lymphoproliferative disorders: a therapeutic target?

PURPOSE OF REVIEW: Several recent studies have focused on the role of angiogenesis in hematologic malignancies. This review specifically discusses angiogenesis in lymphoproliferative disorders, with a special emphasis on the most recent publications. The novel therapeutic strategies arising from advances in this field are reviewed, and the potential pitfalls of these therapies are also discussed. RECENT FINDINGS: Recent publications confirm that angiogenesis and angiogenic factors are increased in lymphoproliferative disorders. In addition, several studies have demonstrated that angiogenesis is directly involved in the pathogenesis of these disorders. SUMMARY: Knowledge of angiogenesis in lymphoproliferative disorders has increased substantially in the past few years. Angiogenic factors such as vascular endothelial growth factor have been shown to be important in the progression or maintenance of lymphoproliferative disorders. Targeting of these factors is therefore a promising new therapeutic approach. Hematopoietic angiogenesis is a nascent field, however, and its concepts are still evolving. A systematic approach to understanding and characterizing the angiogenic phenotype is required for the design of efficacious antiangiogenic therapeutic regimens.     

The chemokine system in allogeneic stem-cell transplantation: a possible therapeutic target?

Further improvements in allogeneic stem-cell transplantation will probably depend on a better balance between immunosuppression to control graft-versus-host disease and immunological reconstitution sufficient to ensure engraftment, reduction of infection-related mortality and maintenance of post-transplant antileukemic immune reactivity. The chemokine network is an important part of the immune system, and, in addition, CXCL12/CXCR4 seem to be essential for granulocyte colony-stimulating factor-induced stem-cell mobilization. Partial ex vivo graft T-cell depletion based on the expression of specific chemokine receptors involved in T-cell recruitment to graft-versus-host disease target organs may also become a future therapeutic strategy; an alternative approach could be pharmacological inhibition (single-receptor inhibitors or dual-receptor inhibitors) in vivo of specific chemokine receptors involved in this T-cell recruitment. Future clinical studies should therefore be based on a better characterization of various immunocompetent cells, including their chemokine receptor profile, both in the allografts and during post-transplant reconstitution.     

Mechanisms of disease: chronic inflammation and cancer in the pancreas--a potential role for pancreatic stellate cells?

Late diagnosis and ineffective therapeutic options mean that pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer. The identification of genetic alterations facilitated the launch of the Pancreatic Intraepithelial Neoplasm nomenclature, a standardized classification system for pancreatic duct lesions, but the factors that contribute to the development of such lesions and their progression to high-grade neoplasia remain obscure. Age, smoking, obesity and diabetes confer increased risk of PDA, and the presence of chronic pancreatitis is a consistent risk factor for pancreatic cancer. It is hypothesized that chronic inflammation generates a microenvironment that contributes to malignant transformation in the pancreas, as is known to occur in other organs. Pancreatic stellate cells (PSCs) are the main mediator of fibrogenesis during chronic pancreatitis, but their contribution to the development of PDA has not been elucidated. Data now suggest that PSCs might assume a linking role in inflammation-associated carcinogenesis through their ability to communicate with inflammatory cells, acinar cells, and pancreatic cancer cells in a complicated network of interactions. In this Review, the role of PSCs in the process of inflammation-associated carcinogenesis is discussed and new potential treatment options evaluated.