Pulmonary hypertension is characterized by hypertrophy and hyperplasia of vascular smooth muscle occurring via an unknown mechanism. Cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) are expressed under inflammatory conditions and produce mediators that regulate growth in some tissues. We have therefore addressed the question of COX-2 and iNOS involvement in proliferation of human and rat pulmonary artery (PA) smooth-muscle cells (SMC). Interleukin (IL)-1beta suppressed proliferation of both human and rat PA SMC. Moreover, IL-1beta induced COX-2 expression in both cell types. By contrast, IL-1beta stimulated the expression of iNOS protein in rat cells only. COX-2 induced in human cells inhibited proliferation, whereas COX-2 products in rat cells were without affect. However, iNOS activity in rat cells suppressed their proliferation. We conclude that human and rat evolution has diverged such that COX-2 and iNOS, although induced by the same mediator, have different levels of activity and functions in the two species. In humans, induction of COX-2 during pulmonary hypertension may be beneficial for long-term treatment of this disease.

Cardiac amyloidosis is a rare but life-threatening group of disorders caused by the extracellular deposition of misfolded amyloid fibrils in cardiac tissue. Amyloid accumulation leads to cardiomyocyte toxicity, extracellular volume expansion, and ventricular pseudohypertrophy. Two types of amyloid protein are thought to be responsible for most disorders: immunoglobulin light chain, which causes light chain amyloidosis (AL); and transthyretin (TTR), which causes transthyretin amyloidosis (ATTR), of which there are two types: hereditary (hATTR) or wild-type (ATTRwt). Despite increasing clinical recognition of the disease, cardiac amyloidosis remains underdiagnosed. This article explores the epidemiology of AL and ATTR and the noninvasive techniques that help to improve diagnosis of the disorder. Cardiac amyloidosis is associated with mixed phenotype symptoms of polyneuropathy and cardiomyopathy which can lead to multiple misdiagnoses. As a result, patients can wait between 2 and 4 years for a correct diagnosis. Early diagnosis may be aided by recognising red flag symptom clusters. These include family history; neuropathy and sensory involvement; bilateral carpal tunnel syndrome; early autonomic dysfunction and gastrointestinal complaints; heart failure (HF) with preserved ejection fraction (HFpEF; without hypertension); cardiac hypertrophy, arrhythmias, ventricular blocks, right-sided or biventricular HF, or cardiomyopathy; renal abnormalities; and vitreous opacities. Noninvasive imaging techniques have increasingly been used as an alternative to biopsy to diagnose cardiac amyloidosis with the hope of allowing physicians to provide targeted therapy for these patients. Techniques include speckle tracking echocardiography, cardiac MRI, and nuclear scintigraphy, together with biomarkers such as N-terminal pro-brain natriuretic peptide and hepatocyte growth factor (HGF). It is hoped that greater understanding of patients with ATTR may lead to increased awareness of the disorder and improve patient outcomes.

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Free radicals, such as superoxide (O 2 . -) and nitric oxide (NO . ), have long been thought to have deleterious roles in various inflammatory diseases. However, specificity problems associated with the use of inhibitors has made it difficult to define the precise, and often complex, pro-or anti-inflammatory roles of these molecules in experimental settings. Reporting in The Journal of Experimental Medicine, Krieglstein and co-workers used gene-targeting technology to investigate the role of free radical-producing enzymes in a mouse model of inflammatory bowel disease (IBD). Interestingly, they found diverging roles for NO . and O 2 . -. Using dextran sulfate sodium (DSS)-induced colitis as a model of IBD, the authors compared the response of wild-type mice with three gene-targeted mutants: mice deficient in inducible nitric oxide synthase (iNOS -/-) or the p47phox subunit of NADPH oxidase (p47phox -/-), or transgenic mice which overexpress superoxide dismutase (SOD). The relative protective or adverse effects of targeting these genes was determined by measuring various indicators of colitis after 7 days of DSS treatment.The authors found that the iNOS-deficient mice were protected against DSS-induced colitis, whereas overexpression of SOD (which catalyses the removal of O 2 . -) was associated with exacerbated injury, and mice genetically deficient in p47phox had similar injury to the wild-type mice.It seems that NO . and O 2 .have divergent roles -NO . proinflammatory, O 2 .anti-inflammatory -in DDS-induced colitis. Although NO . can act beneficially as an antioxidant by scavenging peroxyl radicals and terminating lipid peroxidation, Krieglstein et al. show that it can be pro-inflammatory in certain settings. Whether NO . contributes directly or indirectly to the inflammatory process (i.e. through the formation of peroxynitrite or perhaps nitroxyl anions) remains to be determined. Nick LambReferences and links ORIGINAL RESEARCH PAPER Krieglstein, C. F. et al. Regulation of murine intestinal inflammation by reactive metabolites of oxygen and nitrogen: divergent roles of superoxide and nitric oxide.