Cigarette smoke condensate aggravates renal injury in the renal ablation model

BACKGROUND: Cigarette smoking increases the risk of progression of diabetic and non-diabetic renal diseases. The mechanisms underlying the adverse effects of smoking are largely unknown. We examined the subtotally nephrectomized rat (i) to investigate whether components of cigarette smoke dissolved in acetone (cigarette smoke condensate) aggravate structural renal damage and (ii) to establish whether this provides an animal model that can be used to investigate potential pathomechanisms of cigarette smoke-induced renal damage. Since nicotine activates the sympathetic nerve system in humans, we investigated whether interference with this system modulates the effects of cigarette smoke condensate on the damaged kidney. METHODS: One group of Sprague-Dawley rats was subtotally nephrectomized (SNX). Acetone (SNX + solvent) or cigarette smoke condensate (SNX + cigarette) was applied daily to the oral mucosa. Another group of Sprague-Dawley rats was sham-operated and received the same treatments (sham + solvent, sham + cigarette). To investigate whether increased activity of the sympathetic nerve system is involved, the remnant kidney was denervated by microsurgical technique in one SNX + cigarette group. The control group for this intervention was a solvent-treated SNX group with denervated remnant kidney. Blood pressure (BP) was measured weekly by tail plethysmography. The experiment was terminated after 12 weeks. Structural renal damage was assessed by morphometric techniques (indices of glomerulosclerosis, tubulointerstitial and vascular damage) and urinary albumin and endothelin-1 excretion were measured. RESULTS: Indices of structural renal damage were increased in all SNX-groups. Treatment with cigarette smoke condensate further increased the indices of glomerulosclerosis and tubulointerstitial damage in SNX, but not sham-operated rats. This increase was completely prevented by renal denervation. No differences in systemic blood pressure were observed in the different SNX groups. Urinary albumin excretion went in parallel with the indices of glomerulosclerosis and tubulointerstitial damage and urinary endothelin-1 excretion was significantly increased in SNX + cigarette animals. CONCLUSION: These findings document that acetone soluble components in cigarette smoke aggravate glomerulosclerosis and tubulointerstitial damage in the renal ablation model. Renal injury induced by cigarette smoke condensate in this model is reversed by renal denervation. We conclude that cigarette smoke-induced renal damage is due, at least in part, to activation of the sympathetic nerve system.     

MCP-1 induces inflammatory activation of human tubular epithelial cells: involvement of the transcription factors,nuclear factor-kappaB and activating protein-1

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine synthesized by several cell types, e.g., inflammatory cells, such as monocytes, and resident renal cells, such as human tubular epithelial cells (TECs). Besides induction of monocyte recruitment, MCP-1 has been suggested to induce non-leukocytes to produce cytokines and adhesion molecules. Inflammation of the tubulointerstitium is a hallmark of many renal diseases and contributes to progression of renal failure; the purpose therefore of this study was to investigate the influence of MCP-1 on markers of inflammatory activation in human TECs. MCP-1 stimulated interleukin-6 (IL-6) secretion and intercellular adhesion molecule-1 (ICAM-1) synthesis in a time- and dose-dependent manner. In parallel, MCP-1 increased IL-6 and ICAM-1 mRNA expression in human TECs. Pretreatment with pertussis toxin, GF109203X, BAPTA-AM, and pyrrolidine dithiocarbamate inhibited MCP-1-dependent IL-6 and ICAM-1 synthesis, suggesting the involvement of Gi-proteins, protein kinase C, intracellular Ca(2+), and nuclear factor-kappaB (NF-kappaB) in MCP-1 signaling. Using electrophoretic gel mobility shift assay, we observed that MCP-1 stimulated binding activity of NF-kappaB. Binding activity of the activator protein-1 (AP-1), which has been implicated to regulate induction of the IL-6 gene together with NF-kappaB, was also stimulated by MCP-1. In the present experiments, NF-kappaB and AP-1 were involved in the MCP-1-mediated induction of IL-6, as demonstrated by cis element double-stranded (decoy) oligonucleotides (ODN). In contrast to IL-6 release, MCP-1-induced ICAM-1 expression was predominantly dependent on NF-kappaB activation. These results document for the first time that MCP-1 induces an inflammatory response in human TECs. This may be an important new mechanism in the pathogenesis of tubulointerstitial inflammation.     

Different acute-phase response in newborns and infants undergoing surgery

In a prospective clinical study, we investigated the inflammatory response in 88 neonatal subjects (43 boys and 45 girls) who underwent major abdominal surgery owing to congenital malformation involving the gastrointestinal tract and compared it with the response in 20 infants (8 boys, 12 girls; mean age, 4 mo) who underwent elective surgery for resolution of an existing temporary stoma. In both groups, plasma levels of endotoxin, IL-6, and C-reactive protein as well as leukocyte counts were determined during and after surgery. Endotoxin was measured by the Limulus amebocyte test, IL-6 by ELISA, and C-reactive protein by nephelometry. Statistical analyses were performed using the Wilcoxon signed-rank test. A significant increase in circulating endotoxin and a leukocyte shift was observed in the infant group only. Postoperatively, IL-6 levels peaked between 2 and 6 h and C-reactive protein after 24 h in the infant group. In contrast, no significant increase in the levels of endotoxin, IL-6, and C-reactive protein in plasma were observed during and after surgery in the neonatal subjects, except those with gastroschisis. Newborns with gastroschisis developed an inflammatory response after surgery that was less pronounced than the response of infants older than 4 mo. The finding that endotoxemia in newborns does not follow surgical trauma is most likely because of the absence of bacterial colonization of the gastrointestinal tract.     

Effects of smoking on systemic and intrarenal hemodynamics: influence on renal function

In recent years, it has become apparent that smoking has a negative impact on renal function, being one of the most important remediable renal risk factors. It has been shown clearly that the risk for high-normal urinary albumin excretion and microalbuminuria is increased in smoking compared with nonsmoking subjects of the general population. Data from the Multiple Risk Factor Intervention Trial indicate that at least in men, smoking increases the risk to reach end-stage renal failure. Smoking is particularly "nephrotoxic" in older subjects, subjects with essential hypertension, and patients with preexisting renal disease. Of interest, the magnitude of the adverse renal effect of smoking seems to be independent of the underlying renal disease. Death-censored renal graft survival is decreased in smokers, indicating that smoking also damages the renal transplant. Cessation of smoking has been shown to reduce the rate of progression of renal failure both in patients with renal disease and in patients with a renal transplant. The mechanisms of smoking-induced renal damage are only partly understood and comprise acute hemodynamic (e.g., increase in BP and presumably intraglomerular pressure) and chronic effects (e.g., endothelial cell dysfunction). Renal failure per se leads to an increased cardiovascular risk. The latter is further aggravated by smoking. Particularly, survival of smokers with diabetes on hemodialysis is abysmal.     

Respiratory monitoring in neuromuscular disease - capnography as an additional tool?

Daytime complaints like fatigue, sleepiness and cognitive dysfunction in neuromuscular disease can be due to nocturnal hypercapnia and hypoxemia. Daytime respiratory diagnostics does not reflect sleep disordered breathing. Nocturnal pulse oxymetry and capnography were performed in 11 patients (15-75 years old) with different slowly progressive neuromuscular diseases. Only four patients complained of dyspnea. Pulmonary function was abnormal in three patients. Blood gas samples showed a hypoxemia in three patients. Pulse oxymetry results were pathological in six patients. Nine patients presented abnormal capnographies. According to these results either nocturnal oxygen application was initiated or ventilatory parameters were modified. Daytime symptoms and muscular strength improved markedly. Capnography and pulse oxymetry should be performed during the course of neuromuscular disease to detect respiratory insufficiency. Capnography seems to be a more sensitive indicator for respiratory impairment especially when artificial ventilation has been initiated.     

Serum thyrotropin concentrations and bioactivity during sleep deprivation in depression

BACKGROUND: One night of sleep deprivation induces a brief remission in about half of depressed patients. Subclinical hypothyroidism may be associated with depression, and changes in hypothalamic-pituitary-thyroid function may affect the mood response to sleep deprivation. We wished to define precisely the status of the hypothalamic-pituitary-thyroid axis of depressed patients during sleep deprivation and the possible relationship of hypothalamic-pituitary-thyroid function to the mood response. METHODS: We studied 18 patients with major depressive disorder and 10 normal volunteers. We assessed mood before and after sleep. We measured serum thyrotropin every 15 minutes during the night of sleep deprivation, thyrotropin bioactivity, the thyrotropin response to protirelin the next afternoon, and other indexes of hypothalamic-pituitary-thyroid function. To determine if the changes were limited to the hypothalamic-pituitary-thyroid axis, we measured serum cortisol, which also has a circadian secretory pattern. RESULTS: Nocturnal serum thyrotropin concentrations were consistently higher in responders, entirely because of elevated levels in the women reponders. Responders had exaggerated responses to protirelin the next afternoon. The bioactivity of thyrotropin in nonresponders was significantly greater than in responders (F(1,8. 99) = 7.52; P =.02). Other thyroid indexes and serum cortisol concentrations were similar among groups. CONCLUSIONS: Depressed patients have mild compensated thyroid resistance to thyrotropin action, not subclinical autoimmune primary hypothyroidism. Sleep deprivation responders compensate by secreting more thyrotropin with normal bioactivity; nonresponders compensate by secreting thyrotropin with increased bioactivity.     

The effect of feeding on cerebrospinal fluid corticotropin-releasing hormone levels in humans

Corticotropin-releasing hormone (CRH) is a neuropeptide thought to play a role in appetite regulation. In this report, we used a serial cerebrospinal fluid (CSF) sampling technique to examine the relationship between CSF CRH, plasma ACTH and cortisol and perceptions of hunger and satiety in fasting and sated volunteers. CSF was withdrawn continuously from 11:00 AM to 5:00 PM via an indwelling subarachnoid catheter. Blood was withdrawn every 10 min via an antecubital vein catheter. Fed subjects received a meal at 1:00 PM. Subjects who were fed had lower post-prandial ratings on hunger scales and higher ratings on satiety scales. Fed subjects also had slightly lower levels of CSF CRH after feeding. Furthermore, fed subjects had higher ACTH and cortisol concentrations in the first 3 h; by the fourth h the opposite was true. Our findings do not support the hypothesis that CNS CRH is a central satiety factor in the human. Instead our findings of slightly diminished CSF CRH levels after feeding may be accounted for by the rises in glucocorticoids and their associated negative feedback effects on CNS CRH. Alternatively, our findings could also reflect changes in CRH levels associated with feeding in multiple brain areas and in the spinal cord with the net effect being in the negative direction.