Effect of wood smoke exposure on vascular function and thrombus formation in healthy fire fighters.

BACKGROUND: Myocardial infarction is the leading cause of death in fire fighters and has been linked with exposure to air pollution and fire suppression duties. We therefore investigated the effects of wood smoke exposure on vascular vasomotor and fibrinolytic function, and thrombus formation in healthy fire fighters. METHODS: In a double-blind randomized cross-over study, 16 healthy male fire fighters were exposed to wood smoke (~1 mg/m³ particulate matter concentration) or filtered air for one hour during intermittent exercise. Arterial pressure and stiffness were measured before and immediately after exposure, and forearm blood flow was measured during intra-brachial infusion of endothelium-dependent and -independent vasodilators 4-6 hours after exposure. Thrombus formation was assessed using the ex vivo Badimon chamber at 2 hours, and platelet activation was measured using flow cytometry for up to 24 hours after the exposure. RESULTS: Compared to filtered air, exposure to wood smoke increased blood carboxyhaemoglobin concentrations (1.3% versus 0.8%; P < 0.001), but had no effect on arterial pressure, augmentation index or pulse wave velocity (P > 0.05 for all). Whilst there was a dose-dependent increase in forearm blood flow with each vasodilator (P < 0.01 for all), there were no differences in blood flow responses to acetylcholine, sodium nitroprusside or verapamil between exposures (P > 0.05 for all). Following exposure to wood smoke, vasodilatation to bradykinin increased (P = 0.003), but there was no effect on bradykinin-induced tissue-plasminogen activator release, thrombus area or markers of platelet activation (P > 0.05 for all). CONCLUSIONS: Wood smoke exposure does not impair vascular vasomotor or fibrinolytic function, or increase thrombus formation in fire fighters. Acute cardiovascular events following fire suppression may be precipitated by exposure to other air pollutants or through other mechanisms, such as strenuous physical exertion and dehydration.

Regulation of Giα protein expression by vasoactive peptides in hypertension: molecular mechanisms.

Guanine nucleotide regulatory proteins (G proteins) play a key role in the regulation of various signal transduction systems, including adenylyl cyclase/cAMP and phospholipase C (PLC)/phosphatidyl inositol (PI) turnover, which are implicated in the modulation of a variety of physiological functions, such as platelet functions, including platelet aggregation, secretion, and clot formation and cardiovascular functions, including arterial tone and reactivity. Several abnormalities in adenylyl cyclase activity, cAMP levels and G proteins have been shown to be responsible for the altered cardiac performance and vascular functions observed in cardiovascular disease states. The enhanced or unaltered levels of inhibitory G proteins (Giα) and mRNA have been reported in different models of hypertension, whereas Gsα levels are shown to be unaltered. The enhanced levels of Giα proteins precede the development of blood pressure and suggest that overexpression of Gi proteins may be one of the contributing factors for the pathogenesis of hypertension. The levels of vasoactive peptides including ET-1 and Ang II and growth factors are augmented in hypertension and contribute to the enhanced expression of Giα proteins in hypertension. In addition, oxidative stress due to enhanced levels of Ang II and ET-1 is enhanced in hypertension and may also be responsible for the enhanced expression of Giα proteins observed in hypertension. Furthermore, Ang II- and ET-1-induced transactivation of growth factor receptor through the activation of MAP kinase signaling is also shown to contribute to the augmented levels of Giα in hypertension. Thus, it appears that the enhanced levels of vasoactive peptides by increasing oxidative stress and transactivation growth factor receptors enhance MAP kinase activity that contribute to the enhanced expression of Giα proteins responsible for the pathogenesis of hypertension. In this review, we describe the role of vasoactive peptides and the signaling mechanisms responsible for the enhanced expression of Giα proteins in hypertension.

The endothelium: physiological functions and role in microcirculatory failure during severe sepsis.

The endothelium is a highly dynamic cell layer that is involved in a multitude of physiological functions, including the control of vascular tone, the movement of cells and nutrients, the maintenance of blood fluidity and the growth of new vessels. During severe sepsis, the endothelium becomes proadhesive, procoagulant, antifibrinolytic and is characterized by alterations of vasomotor regulation. Most of these functions have been discovered using in vitro and animal models, but in vivo exploration of endothelium in patients remains difficult. New tools to analyze endothelial dysfunction at bedside have to be developed.

Postulated vasoactive neuropeptide autoimmunity in fatigue-related conditions: a brief review and hypothesis.

Disorders such as chronic fatigue syndrome (CFS) and gulf war syndrome (GWS) are characterised by prolonged fatigue and a range of debilitating symptoms of pain, intellectual and emotional impairment, chemical sensitivities and immunological dysfunction. Sudden infant death syndrome (SIDS) surprisingly may have certain features in common with these conditions. Post-infection sequelae may be possible contributing factors although ongoing infection is unproven. Immunological aberration may prove to be associated with certain vasoactive neuropeptides (VN) in the context of molecular mimicry, inappropriate immunological memory and autoimmunity. Adenylate cyclase-activating VNs including pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) act as hormones, neurotransmitters, neuroregulators, immune modulators and neurotrophic substances. They and their receptors are potentially immunogenic. VNs are widely distributed in the body particularly in the central and peripheral nervous systems and have been identified in the gut, adrenal gland, blood cells, reproductive system, lung, heart and other tissues. They have a vital role in maintaining cardio-respiratory function, thermoregulation, memory, concentration and executive functions such as emotional responses including social cues and appropriate behaviour. They are co-transmitters for a number of neurotransmitters including acetylcholine and gaseous transmitters, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system against toxic assault as well as being important in the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of certain fatigue-related syndromes based on loss of immunological tolerance to these VNs or their receptors following infection, other events or de novo resulting in significant pathophysiology possibly mediated via CpG fragments and heat shock (stress) proteins. These conditions extend the public health context of autoimmunity and VN dysregulation and have implications for military medicine where radiological, biological and chemical agents may have a role in pathogenesis. Possible treatment and prevention options are considered.

Cardiac allograft preservation using donor-shed blood supplemented with L-arginine.

BACKGROUND: Despite improved preservation techniques, myocardial and endothelial dysfunction persists after cardiac transplantation. L-arginine has been shown to decrease endothelial injury in several models of ischemia and reperfusion. We assessed the effects of L-arginine on allograft preservation in a porcine model of cardiac transplantation. METHODS: Orthotopic cardiac transplants were performed in Yorkshire pigs. Hearts were randomly arrested with high potassium cardioplegia with or without L-arginine at a dose of 2.5 mmol/liter (LARGlow) and 5.0 mmol/liter. Donor-shed blood was collected at the time of organ harvest and intermittently perfused throughout the storage period. Coronary endothelial function was assessed at baseline and after reperfusion by measuring the change in coronary blood flow after exposure to acetylcholine or nitroglycerin. Pressure-volume relationships before and after transplant were evaluated with conductance catheter measurements. Myocardial biopsy specimens were assessed for inflammatory markers of cellular injury. RESULTS: High-dose L-arginine uniformly resulted in ischemic contracture in all hearts, and there was no return of function in any hearts after storage. The low-dose L-arginine group had a greater ability to wean off cardiopulmonary bypass and displayed improved recovery of left ventricular function. Control animals had a 26% reduction in coronary flow compared with 13% for LARGlow. LARGlow resulted in decreased release of inflammatory cytokines compared with control. CONCLUSIONS: Low-dose L-arginine preserves myocardial and endothelial function and decreases endothelial injury when it is used as a supplement to intermittent donor blood perfusion. In contrast, high-dose L-arginine resulted in severe endothelial injury and an inability to recover ventricular function after 5 hours of global ischemia.

Circulating autoantibodies to oxidized LDL correlate with impaired coronary endothelial function after cardiac transplantation.

OBJECTIVE: The oxidative modification of low density lipoprotein (LDL) may play a role in the pathogenesis of transplant-associated arteriosclerosis. Oxidized LDL (OxLDL) is immunogenic as well as atherogenic, and the level of autoantibodies to OxLDL has been taken as an index of the oxidant state of LDL. Because endothelial dysfunction is key in the initiation of transplant-associated arteriosclerosis, we postulated that the level of OxLDL autoantibody is associated with the degree of impairment of coronary endothelial function. METHODS AND RESULTS: Coronary endothelium-dependent dilation was assessed by using intracoronary acetylcholine and endothelium-independent dilation by nitroglycerin in 36 cardiac transplant recipients within 1 year of transplantation. The coronary responses to acetylcholine ranged from -37% (vasoconstriction) to 31% (vasodilation), and the responses to nitroglycerin ranged from 0% to 42% (vasodilation). The coronary vasomotor response to acetylcholine was significantly and inversely related to OxLDL autoantibody levels (r=-0.43, P<0.01) but not LDL levels (r=-0.04, P=0.83) or circulating OxLDL levels detected by monoclonal antibody EO6 (r=-0.27, P=0.11). The coronary artery response to nitroglycerin was not related to levels of OxLDL autoantibodies, LDL, or EO6 (all P=NS). CONCLUSIONS: Autoantibodies to OxLDL are increased in patients with coronary endothelial dysfunction in the first year after cardiac transplantation. The oxidative modification of LDL by inducing endothelial dysfunction in cardiac transplant recipients may be a critical step in the atherogenic effects of LDL and may provide a potential target for therapy.

Calretinin immunoreactivity in cholinergic motor neurones, interneurones and vasomotor neurones in the guinea-pig small intestine.

Immunoreactivity for calretinin, a calcium-binding protein, was studied in neurones in the guinea-pig small intestine. 26 +/- 1% of myenteric neurones and 12 +/- 3% of submucous neurones were immunoreactive for calretinin. All calretinin-immunoreactive neurones were also immunoreactive for choline acetyltransferase and hence are likely to be cholinergic. In the myenteric plexus, two subtypes of Dogiel type-I calretinin-immunoreactive neurones could be distinguished from their projections and neurochemical coding. Some calretinin-immunoreactive myenteric neurones had short projections to the tertiary plexus, and hence are likely to be cholinergic motor neurones to the longitudinal muscle. Some of these cells were also immunoreactive for substance P. The remaining myenteric neurones, immunoreactive for calretinin, enkephalin, neurofilament protein triplet and substance P, are likely to be orad-projecting, cholinergic interneurones. Calretinin immunoreactivity was also found in cholinergic neurones in the submucosa, which project to the submucosal vasculature and mucosal glands, and which are likely to mediate vasodilation. Thus, calretinin immunoreactivity in the guinea-pig small intestine is confined to three functional classes of cholinergic neurones. It is possible, for the first time, to distinguish these classes of cells from other enteric neurones.