The relationship between clinical phenotype and kallikrein-kinin bioregulation in different forms of arthritis.

Objective: Patients with rheumatoid arthritis (RA) have shown increased levels of neutrophils generating kallikrein-kinin peptides in blood which are potent mediators of inflammation. This study investigated the association between the bioregulation of kinin-mediated inflammation with the clinical, quality of life, and imaging characteristics (e.g.

Remote ischaemic preconditioning down-regulates kinin receptor expression in neutrophils of patients undergoing heart surgery.

Objectives: Remote ischaemic preconditioning (RIPC) may protect distant organs against ischaemia-reperfusion injury. We investigated the impact of RIPC on kinin receptor expression in neutrophils following RIPC in patients undergoing coronary artery bypass grafting (CABG).

Methods: Patients undergoing elective CABG with cardiopulmonary bypass (CPB) were randomized to RIPC (n = 15) or control (n = 15) groups.

Adverse reactions to the sulphite additives.

Sulphites are widely used as preservative and antioxidant additives in the food and pharmaceutical industries. Exposure to sulphites has been reported to induce a range of adverse clinical effects in sensitive individuals, ranging from dermatitis, urticaria, flushing, hypotension, abdominal pain and diarrhoea to life-threatening anaphylactic and asthmatic reactions. Exposure to the sulphites arises mainly from the consumption of foods and drinks that contain these additives; however exposure may also occur through the use of pharmaceutical products, as well as in occupational settings.

Effects of the demethylating agent, 5-azacytidine, on expression of the kallikrein-kinin genes in carcinoma cells of the lung and pleura.

Tissue kallikrein (KLK1) and plasma kallikrein (KLKB1) may regulate the growth and proliferation of tumours of the lung and pleura, through the generation of kinin peptides that signal through the kinin B(1) (BDKRB1) and B(2) (BDKRB2) receptors. The development and progression of cancer results from genetic mutations, as well as epigenetic changes that include methylation of DNA at CpG islands. The aim of this study was to assess whether expression of the kallikrein-kinin genes in lung cancer and mesothelioma cells is regulated by DNA methylation.

Lys-des[Arg9]-bradykinin alters migration and production of interleukin-12 in monocyte-derived dendritic cells.

This study tested the hypothesis that proinflammatory kinin peptides are involved in modulating human dendritic cell (DC) function. Inflammation is accompanied by an increased maturation of DCs and the generation of kinins, particularly Lys-des[Arg(9)]-bradykinin (Lda-BK). We assessed the role of Lda-BK in the activation and migration of human monocyte-derived DCs (hMo-DCs) matured through the use of LPS, TNF-α + IL-1β, or CD40 ligand.

Remote ischemic preconditioning stimulus decreases the expression of kinin receptors in human neutrophils.

Background: Remote ischemic preconditioning (RIPC) has been shown to reduce ischemic-reperfusion injury and is induced by brief forearm ischemia. Kinins are known to be involved in RIPC and act via the G protein coupled B1 and B2 receptors. Interaction of the kinins with their respective receptors causes receptor internalization, thereby reducing the potential for further activation.

Prostaglandin E2 and cysteinyl leukotriene concentrations in sputum: association with asthma severity and eosinophilic inflammation.

Background: Inflammation of the airways in asthma is associated with the production of cysteinyl leukotrienes (cysLT), prostaglandin (PG)E(2), 8-isoprostane, nitric oxide and other mediators. However, the relationship between asthma severity or eosinophilic inflammation and the concentrations of mediators in sputum is unclear.

Objective: To assess sputum PGE(2), cysLT, 8-isoprostane and nitrate concentrations, as well as urinary leukotriene (LT)E(4) and 9alpha,11beta-prostaglandin (PG)F(2) concentrations, in patients with differing severities of asthma and eosinophilic or non-eosinophilic airway inflammation.

Clinical effects of sulphite additives.

Sulphites are widely used as preservative and antioxidant additives in the food and pharmaceutical industries. Topical, oral or parenteral exposure to sulphites has been reported to induce a range of adverse clinical effects in sensitive individuals, ranging from dermatitis, urticaria, flushing, hypotension, abdominal pain and diarrhoea to life-threatening anaphylactic and asthmatic reactions. Exposure to the sulphites arises mainly from the consumption of foods and drinks that contain these additives; however, exposure may also occur through the use of pharmaceutical products, as well as in occupational settings.

Kallikreins, kininogens and kinin receptors on circulating and synovial fluid neutrophils: role in kinin generation in rheumatoid arthritis.

Objectives: Neutrophils traffic into and have the capacity to generate kinins in SF of RA patients. The aim of this study was to assess the expression of kallikreins, kininogens and kinin receptors in circulating and SF neutrophils, as well as synovial tissue of RA patients, and to assess kinin generation in SF.

Methods: Neutrophils were isolated from blood and SF of RA patients and blood of healthy volunteers.

Increases in urinary 9alpha,11beta-prostaglandin f2 indicate mast cell activation in wine-induced asthma.

Background: Wine-induced asthmatic symptoms may be caused by sulphite additives. Prostaglandin (PG)D2 and cysteinyl leukotrienes (cysLT) are important mediators of asthmatic responses. To determine whether the sulphite additives in wine alter the production of PGD2 and cysLT, asthmatic patients with compelling histories of wine sensitivity were challenged with high- and low-sulphite wines; the urinary metabolites of PGD2 and cysLT were measured before and after challenge.

Epigenetic regulation of human epithelial cell cancers.

Cancer is the second leading cause of death in industrialized countries, with epithelial cell cancers (carcinomas) representing approximately 85% of all diagnosed cancers. The 5-year survival rate for many carcinomas remains low, highlighting the requirement for improved diagnosis and more effective therapies. Epigenetic modifications that do not involve changes in the DNA sequence, but result in changes in gene expression, are rapidly being realized as important in carcinogenesis.

Expression of kinin receptors on eosinophils: comparison of asthmatic patients and healthy subjects.

Eosinophils contribute to asthmatic airway inflammation by releasing cysteinyl leukotrienes (cysLT) and other inflammatory mediators, and bradykinin (BK) induces bronchoconstriction in asthmatic patients. The aims of this study were to investigate kinin receptor expression on eosinophils of asthmatic and healthy subjects and to assess the effects of kinin stimulation on eosinophils, which were isolated from peripheral blood of asthmatic (n=27) and healthy subjects (n=14). Kinin B(1) and B(2) receptors (B(1)R and B(2)R, respectively) and mRNA expression were investigated by quantitative confocal microscopy, flow cytometry, and RT-PCR.

Expression of tissue and plasma kallikreins and kinin B1 and B2 receptors in lung cancer.

Tissue kallikrein (hK1) and plasma kallikrein (PK, hKB1) are serine proteases that produce biologically active kinin peptides from endogenous kininogen substrates. There is evidence linking the kallikreins and the mitogenic kinin peptides to carcinogenesis. The aim of this study was to investigate the expression of tissue prokallikrein (pro-hK1), plasma prekallikrein (PPK, pre-hKB1) and kinin B1 and B2 receptor proteins in different subtypes of lung cancer.

Tolerance and rebound with zafirlukast in patients with persistent asthma.

Background: The potential for tolerance to develop to zafirlukast, a cysteinyl leukotriene (CysLT) receptor antagonist (LRA) in persistent asthma, has not been specifically examined.

Objective: To look for any evidence of tolerance and potential for short-term clinical worsening on LRA withdrawal. Outcome measures included changes in; airway hyperresponsiveness to inhaled methacholine (PD20FEV1), daily symptoms and peak expiratory flows (PEF), sputum and blood cell profiles, sputum CysLT and prostaglandin (PG)E2 and exhaled nitric oxide (eNO) levels.

Cyclooxygenase-2 gene polymorphisms in an Australian population: association of the -1195G > A promoter polymorphism with mild asthma.

Background: Cyclooxygenase (COX)-2 is an inducible enzyme responsible for catalysing the formation of prostaglandins (PGs) in settings of inflammation. Single nucleotide polymorphisms (SNPs) of the COX-2 gene may influence gene transcription and PG production in the asthmatic airway.

Objective: To evaluate the frequencies of COX-2 SNPs in an Australian Caucasian population, and determine potential associations between common COX-2 promoter SNPs and asthma, asthma severity and aspirin-intolerant asthma (AIA).

Expression of kallikrein-related peptidases (KRP/hK5, 7, 6, 8) in subtypes of human lung carcinoma.

Lung cancer is currently the leading cause of cancer mortality worldwide. Expression of kallikrein-related peptidases (KRP/hK/KLK) may be induced during lung carcinogenesis. To test the hypothesis that KRP/hK, previously identified in the skin (KRP/hK5, 7) and brain (KRP/hK6, 8), are expressed in lung tumours, experiments were designed to investigate their localization in four malignant sub-types of human lung cancer.

Omalizumab (Xolair) in patients with steroid-resistant asthma: lessons to be learnt.

Very severe asthma and local pulmonary steroid resistance causes major problems for patients, physicians and the health system at large. It usually results in multiple admissions to hospital and high morbidity. Omalizumab was used to treat such patients with success.

Molecular genetics and mechanisms of apoptosis in carcinomas of the lung and pleura: therapeutic targets.

Cancers of the lung and pleura remain a major cause of cancer deaths, both in men and women, with strong causal relationships between cigarette smoking and asbestos fibres, and deaths from lung cancer and mesothelioma, respectively. The poor survival rates for small cell lung cancer and mesotheliomas argue powerfully for greater understanding of mechanisms of carcinogenesis, genetic abnormalities and the role of tumour suppressor genes and proteins in carcinomas of the lung and pleura. Despite progress in the development of newer cytotoxic drugs, lung cancer remains a lethal disease.

Physiological concentrations of transforming growth factor beta1 selectively inhibit human dendritic cell function.

In this study the effects of different in vitro conditioning with transforming growth factor (TGF) beta1 on human monocyte-derived DC maturation (hMo-DC) were investigated. hMo-DC differentiated in the presence of physiologically relevant concentrations of TGFbeta1 (2 ng/ml) failed to undergo complete maturation despite adequate stimulation with LPS or LPS+IFNgamma. These hMo-DC did not produce IL-12p70 or PGE2, and showed decreased IL-10 and IL-18 production and HLA-DR expression.

Comparison of kinin B(1) and B(2) receptor expression in neutrophils of asthmatic and non-asthmatic subjects.

Kinins have been implicated in the pathophysiology of asthma and activation of kinin receptors stimulates neutrophil chemotaxis. However, the expression of kinin receptors on neutrophils of asthmatic subjects has not been assessed. The aim of this study was to compare the expression of kinin B(1) and B(2) receptor mRNA and proteins in neutrophils of asthmatic and non-asthmatic subjects, and to assess whether inhaled corticosteroid treatment may influence expression of the kinin receptors.

Novel expression of kallikreins, kallikrein-related peptidases and kinin receptors in human pleural mesothelioma.

Malignant mesothelioma is an aggressive cancer of the pleura that is causally related to exposure to asbestos fibres. The kallikrein serine proteases [tissue (hK1) and plasma (hKB1) kallikreins, and kallikrein-related peptidases (KRP/hK2-15)] and the mitogenic kinin peptides may have a role in tumourigenesis. However, it is not known whether hK1, hKB1, KRP/hK proteins or kinin receptors are expressed in pleural mesotheliomas.

Current status of tissue kallikrein inhibitors: importance in cancer.

The past decade has seen an increase in the understanding of the structure and function of protease inhibitors. The molecular basis of the interaction between a variety of biological substrates or synthetic inhibitors and serine proteases of the kallikrein family has provided insights into inhibitor protein-protease reactive site interactions, which have proved of value in the design of new kallikrein inhibitors. This review focuses on the current understanding of the functional status of kallikrein inhibitors, which include a variety of molecules derived from plant, reptile and mammalian sources, as well as synthetic agents.

Changes in bronchial hyperresponsiveness following high- and low-sulphite wine challenges in wine-sensitive asthmatic patients.

Background: Previous studies suggest that challenge of most wine-sensitive asthmatic patients may not result in a reduction in forced expiratory volume in 1 s (FEV(1)).

Objective: The aim of this study was to assess whether changes in bronchial hyperresponsiveness (BHR) occur following wine challenge of asthmatic patients who report sensitivity to wine, and whether such changes could help clarify the role of sulphite additives in wine-induced asthmatic responses.

Methods: Eight self-reporting wine-sensitive asthmatic patients completed double-blind challenges with high- and low-sulphite wines on separate days.

Plasma phospholipase A2 activity in patients with asthma: association with body mass index and cholesterol concentration.

Background: Secretory phospholipases A2 (sPLA2) have functions relevant to asthmatic inflammation, including eicosanoid synthesis and effects on dendritic cells and T cells. The aim of this study was to measure sPLA2 activity in patients with stable and acute asthma and to assess potential associations with body mass index (BMI), and plasma cholesterol and vitamin C concentrations.

Methods: Plasma sPLA2 activity and concentrations of cholesterol and vitamin C were measured in 23 control subjects and 61 subjects with stable asthma (42 mild to moderate, 19 severe).

Expression of kinin B1 and B2 receptors in immature, monocyte-derived dendritic cells and bradykinin-mediated increase in intracellular Ca2+ and cell migration.

The kinins, bradykinin (BK) and Lys-des[Arg(9)]-BK, are important inflammatory mediators that act via two specific G protein-coupled kinins, B(1) and B(2) receptors (B(2)R). Kinins influence the activity of immune cells by stimulating the synthesis of cytokines, eicosanoids, and chemotactic factors. Whether human dendritic cells (DC) express kinin receptors and whether kinins influence DC function are unknown.