Atropine,sodium cromoglycate,and thymoxamine in PGF2 alpha-induced bronchoconstriction in extrinsic asthma.

In six patients with extrinsic bronchial asthma the inhalation of prostaglandin (PG) F2 alpha in a small dosage produced significant bronchoconstriction, whereas PGE2 produced bronchodilatation. In these patients cholinergic blockade with atropine partially inhibited the PGF2 alpha-induced bronchoconstriction, but the alpha-receptor-blocking drug thymoxamine and sodium cromoglycate did not. These results suggest that the effect of PGF2 alpha is mediated through cholinergic receptors in the airways, and this effect is grossly exaggerated in asthma. The failure to inhibit PGF2 alpha-induced bronchoconstriction with sodium cromoglycate and the observation of an inhibitory effect of sodium cromoglycate in both allergic and exercise asthma suggest that locally formed PGF2 alpha may not be the main factor in the pathogenesis of bronchial asthma.     

Time course and attenuation of ischaemia-reperfusion induced oxidative injury by propofol in human renal transplantation

Ischaemia-reperfusion injury resulting from interruption and restoration of blood flow might be related to free radical mediated oxidative stress and inflammation, and subsequently to post-surgery related complications. We studied the impact of renal transplantation on oxidative stress and inflammation by measuring F(2)-isoprostanes and prostaglandin F(2alpha), respectively, during transplantation and post-surgery. Additionally, due to earlier observations, two dissimilar anaesthetic agents (thiopentone and propofol) were compared to determine their antioxidative capacity rather than their anaesthetic properties. Blood samples were collected before, post-intubation, immediately, 30, 60,120, 240 min, and 12 and 24 h after reperfusion. Oxidative stress and inflammatory response were detected by measuring 8-iso-PGF(2alpha) (a major F(2)-isoprostane and a biomarker of oxidative stress) and 15-keto-dihydro-PGF(2alpha) (a major metabolite of PGF(2alpha) and a biomarker of COX-mediated inflammatory response), respectively. Reperfusion of the transplanted graft significantly increased plasma levels of 8-iso-PGF(2alpha). PGF(2alpha) metabolite levels, although elevated, did not reach statistical significance. In addition, significantly lower levels of 8-iso-PGF(2a) were observed in the propofol group compared to the thiopentone group. Together, these findings underline an augmented oxidative stress activity following an inflammatory response after human renal transplantation. Furthermore, propofol a well-known anaesthetic, counteracted oxidative stress by lowering the formation of a major F(2)-isoprostane.     

Cyclooxygenase-mediated prostaglandin F2alpha is decreased in an elderly population treated with low-dose aspirin

Low-dose aspirin (acetylsalicylic acid) is used as prophylaxis against cardiovascular diseases. The effect of aspirin on inflammation and oxidative stress, processes known to be involved in cardiovascular diseases, are not fully known. The cyclooxygenase(COX)-mediated inflammatory indicator prostaglandin F2alpha (PGF2alpha) (15-keto-dihydro-PGF2alpha), cytokine-mediated inflammatory indicators (interleukin-6, high-sensitivity C-reactive protein, serum amyloid A protein), and oxidative stress indicators (8-iso-PGF2alpha, tocopherols) were quantified in men with daily 75 mg of aspirin (n=175) and control men (n=464), all of age 77, in a cross-sectional study. Men treated with aspirin had decreased levels of urinary 15-keto-dihydro-PGF2alpha than controls (P<0.01), independent of possible cardiovascular risk factors. Aspirin-treated men had increased levels of alpha-tocopherol than controls (P<0.05). This is the first study to indicate that low-dose aspirin treatment is associated with decreased levels of PGF2alpha. This observation suggests a possible COX-mediated anti-inflammatory effect of low-dose aspirin, which should be further confirmed by intervention studies.     

Effect of a thromboxane receptor antagonist on PGD2- and allergen-induced bronchoconstriction

In this study we investigated the effect of the selective and potent thromboxane A2 (TxA2) receptor antagonist GR32191 on smooth muscle contraction induced by the TxA2 analogue U46619, prostaglandin (PG) D2, PGF2 alpha, and methacholine (MCh) in guinea pig airways in vitro and the airways response provoked by inhaled PGD2 and MCh in asthmatic subjects in vivo. GR32191 antagonized competitively the contractile responses of all three prostanoids to a similar degree but had no effect on MCh-induced contractions. In asthmatic subjects GR32191, in a single oral dose of 80 mg, did not affect base-line airway caliber or MCh-induced broncho-constriction but caused significant inhibition of PGD2-induced bronchoconstriction, displacing the concentration-response curves to the right by greater than 10-fold. The effect of the same oral dose of GR32191 on allergen-induced immediate bronchoconstriction was subsequently investigated in allergic asthmatic subjects. In individual subjects, GR32191 inhibited to varying degrees the overall bronchoconstrictor response, with the maximum effect occurring between 10 and 30 min after allergen challenge. These studies suggest that prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatics, and that this effect is mediated by stimulation of a thromboxane receptor.     

Partitioning of pulmonary resistance during constriction in the dog: effects of volume history

We assessed the relative changes in airways and lung tissue with bronchoconstriction, and the changes in each during and following a deep inhalation (DI). We partitioned pulmonary resistance (RL) into airway (Raw) and tissue (Vtis) components using alveolar capsules in 10 anesthetized, paralyzed, and open-chested dogs ventilated sinusoidally with 350-ml breaths at 1 Hz. We made measurements before and during bronchoconstriction induced by vagal stimulation or inhalation of histamine or prostaglandin F2 alpha (PGF2 alpha), each of which decreased dynamic compliance by approximately 40%. With histamine and PGF2 alpha the rise in RL was predominantly due to Vtis. With vagal stimulation there was a relatively greater increase in Raw than Vtis. At higher lung volumes, Vtis increases offset falls in Raw, producing higher RL at these volumes before and during constriction with PGF2 alpha and histamine. During constriction with vagal stimulation, the fall in Raw with inflation overrode the rise in Vtis, resulting in a lower RL at the higher compared with the lower lung volume. The changes seen after a DI in the control and constricted states were due to alterations in tissue properties, both viscous and elastic. However, the relative hysteresis of the airways and parenchyma were equal, since Raw, our index of airway size, was unchanged after a DI.     

Prostaglandin F2 alpha increases responsiveness of pulmonary airways in dogs

We studied the effect of prostaglandin F2 alpha (PGF2 alpha) on the responsiveness of pulmonary airways in dogs. Airway responsiveness was assessed by determining the bronchoconstrictor response to increasing concentrations of acetylcholine aerosol delivered to the airways. In each of five dogs, we determined responsiveness during treatment with physiologic saline, histamine, or PGF2 alpha aerosols. The doses of histamine and PGF2 alpha were determined by establishing the largest dose of each which could be given to the dog without causing bronchoconstriction (subthreshold doses). We found that airway responsiveness was not significantly different during histamine treatment than after saline, however, responsiveness increased during treatment with PGF2 alpha. In addition, the hyperresponsiveness induced by PGF2 alpha was prevented by pretreatment with the ganglion blocking drug hexamethonium (5 mg/kg given intravenously). The results show that PGF2 alpha specifically increases the responsiveness of pulmonary airways in doses that do not cause bronchoconstriction, and suggest that the hyperresponsiveness involves a neural mechanism such as increased responsiveness of airway sensory nerves.     

Both cyclooxygenase- and cytokine-mediated inflammation are associated with carotid intima-media thickness

BACKGROUND: Common carotid artery intima-media thickness (CCA-IMT) is a valid index of atherosclerosis, which is viewed as an inflammatory disease. It is unknown if various modes of inflammation (cyclooxygenase [COX]-mediated, cytokine-mediated), oxidative stress and anti-oxidants are independently related to CCA-IMT. METHODS AND RESULTS: We investigated cross-sectional relations between CCA-IMT measured by B-mode ultrasound and COX-mediated inflammation (as measured by 15-keto-dihydro-prostaglandin F(2alpha) [PGF(2alpha)], cytokine-mediated inflammation (interleukin-6 [IL-6], high sensitivity C-reactive protein [hsCRP] and serum amyloid A protein [SAA]), oxidative stress (8-iso-PGF(2alpha), an F(2)-isoprostane; a non-enzymatic, free radical-induced product of arachidonic acid), and tocopherols (anti-oxidants) in a small subset of a population-based sample of elderly men (n=234) stating no use of anti-inflammatory medications. In a backward-stepwise regression analysis of correlates of CCA-IMT (with PGF(2alpha), hsCRP, IL-6, SAA, F(2)-isoprostanes, tocopherols, diabetes, body mass index (BMI), beta-blocker, statin treatment, smoking, hypertension and cholesterol), PGF(2alpha), CRP, beta-blocker treatment, diabetes and BMI were independently associated with CCA-IMT. There were no associations between F(2)-isoprostanes or tocopherols and CCA-IMT in this study. CONCLUSION: This study suggests both COX- and cytokine-mediated inflammation to be independently associated with increased CCA-IMT, implying that there might be more than one mode of inflammation involved in atherogenesis.     

Serum selenium predicts levels of F2-isoprostanes and prostaglandin F2alpha in a 27 year follow-up study of Swedish men

Low concentrations of selenium (Se) predict mortality and cardiovascular diseases in some populations. The effect of Se on in vivo indicators of oxidative stress and inflammation, two important features of atherosclerosis, in human populations is largely unexplored. This study investigated the longitudinal association between serum selenium (s-Se) and a golden standard indicator of oxidative stress in vivo (8-iso-prostaglandin F2alpha, a major F2-isoprostane), an indicator of cyclooxygenase (COX)-mediated inflammation (prostaglandin F2alpha), high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and serum amyloid A protein (SAA) in a follow-up study of 27 years. The s-Se was measured in 615 Swedish men at 50 years of age in a health investigation. The status of oxidative stress and inflammation was evaluated in a re-investigation 27 years later by quantification of urinary 8-iso-PGF2alpha and 15-keto-dihydro-PGF2alpha (a major metabolite of PGF2alpha) and serum hsCRP, SAA and IL-6. Men in the highest quartile of s-Se at age 50 had decreased levels of 8-iso-PGF2alpha compared to all lower quartiles and decreased levels of PGF2alpha compared to all lower quartiles at follow-up. These associations were independent of BMI, diabetes, hyperlipidemia, hypertension, smoking, alpha-tocopherol and beta-carotene at baseline. The s-Se was not associated with hsCRP, SAA or IL-6 at follow-up. In conclusion, high concentrations of s-Se predict reduced levels of oxidative stress and subclinical COX-mediated (but not cytokine-mediated) inflammation in a male population. The associations between Se, oxidative stress and inflammation, respectively, might be related to the proposed cardiovascular protective property of Se.     

Vasomotor responses in MnSOD-deficient mice

MnSOD is the only mammalian isoform of SOD that is necessary for life. MnSOD(-/-) mice die soon after birth, and MnSOD(+/-) mice are more susceptible to oxidative stress than wild-type (WT) mice. In this study, we examined vasomotor function responses in aortas of MnSOD(+/-) mice under normal conditions and during oxidative stress. Under normal conditions, contractions to serotonin (5-HT) and prostaglandin F2alpha (PGF2alpha), relaxation to ACh, and superoxide levels were similar in aortas of WT and MnSOD(+/-) mice. The mitochondrial inhibitor antimycin A reduced contraction to PGF2alpha and impaired relaxation to ACh to a similar extent in aortas of WT and MnSOD(+/-) mice. The Cu/ZnSOD and extracellular SOD inhibitor diethyldithiocarbamate (DDC) paradoxically enhanced contraction to 5-HT and superoxide more in aortas of WT mice than in MnSOD(+/-) mice. DDC impaired relaxation to ACh and reduced total SOD activity similarly in aortas of both genotypes. Tiron, a scavenger of superoxide, normalized contraction to 5-HT, relaxation to ACh, and superoxide levels in DDC-treated aortas of WT and MnSOD(+/-) mice. Hypoxia, which reportedly increases superoxide, reduced contractions to 5-HT and PGF2alpha similarly in aortas of WT and MnSOD(+/-) mice. The vasomotor response to acute hypoxia was similar in both genotypes. In summary, under normal conditions and during acute oxidative stress, vasomotor function is similar in WT and MnSOD(+/-) mice. We speculate that decreased mitochondrial superoxide production may preserve nitric oxide bioavailability during oxidative stress.     

Oxidative stress-inducible antioxidant adaptive response during prostaglandin F2alpha-induced luteal cell death in vivo

Oxidative stress-induced antioxidant adaptive response would be particularly important to cells in high reactive oxygen species (ROS) environments. We aimed to determine the dynamic adaptive response of antioxidant enzymatic systems in sheep corpus luteum (CL) during PGF2alpha-induced luteal cell death. Activities of superoxide dismutase (SOD1 and SOD2), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GSR), and in situ DNA fragmentation were determined in CL at day 10 of the estrous cycle (0 h) and at 12, 24 or 48 h after PGF2alpha injection. A decrease in plasma progesterone concentration was first observed at 6 h after treatment (P < 0.05). Apoptotic cells were rarely observed in the CL at 0 h (less than 0.7%), and their incidence increased (P < 0.01) by 12 h post-PGF2alpha (11.7%) and remained thereafter elevated through 48 h. Activities of SOD1, SOD2, GPX and GSR were not changed at any time points after PGF2alpha treatment. CAT activity increased at 12 h (P < 0.01) and at 24 h (P < 0.05) after PGF2alpha treatment as compared to that at 0 h. These findings demonstrate that PGF2alpha induce luteal cell death without depressing the activity of antioxidant enzymes. It is suggested that transient increase in CAT activity is an adaptive response of the CL to oxidative stress induced by PGF2alpha.     

Cardiopulmonary bypass as a cause of free radical-induced oxidative stress and enhanced blood-borne isoprostanes in humans

Free radicals are believed to be involved in postsurgery-related complications. We studied whether cardiopulmonary bypass (CPB) operation has any immediate impact on the initiation of oxidative stress and inflammatory response by measuring isoprostanes and prostaglandin F2alpha during and 24 h following CPB. The levels of 8-iso-PGF2alpha (a major F2-isoprostane and biomarker of oxidative stress) and 15-keto-dihydro-PGF2alpha (a major metabolite of PGF2alpha and biomarker of inflammatory response) were measured in frequently collected plasma samples before, during, and up to 24 h postsurgery in 21 patients. 8-Iso-PGF2alpha levels significantly increased within 3 min (p <.0001) and continued until 50 min (p <.0001) during CPB. On the contrary, no significant increase of inflammatory response indicator, 15-keto-dihydro-PGF2alpha was found during and up to 24 h postoperatively. These findings establish an increased free radical-induced oxidative stress activity rather than inflammatory response after CPB.     

Isoprostanes, prostaglandins and tocopherols in pre-eclampsia, normal pregnancy and non-pregnancy

This study is designed to evaluate whether oxidative stress and inflammation are involved in severe pre-eclampsia compared to normal pregnancy and non-pregnancy. We have measured plasma and urinary levels of 8-iso-PGF2alpha, a major isoprostane as an indicator of oxidative stress; plasma and urinary 15-keto-dihydro-PGF2alpha, a major metabolite of cyclooxygenase-catalysed PGF2alpha as an indicator of inflammatory response, and plasma -alpha-and -gamma-tocopherol in 18 pre-eclamptic, 19 normal pregnancy and 20 non-pregnant women. Pregnant women had significantly higher levels of 8-iso-PGF2alpha and PGF2alpha metabolite as compared to the non-pregnancy. Levels of 8-iso-PGF2alpha in the pre-eclamptic women did not differ from the normal pregnancy but PGF2alpha metabolite levels were significantly higher in normal pregnancy. On the other hand, gamma-tocopherol levels were significantly lower in pre-eclampsia than normal pregnancy. In contrast, the concentration of alpha-tocopherol was very similar between the groups. alpha-and gamma-tocopherol levels were significantly lower in pregnancy compared to non-pregnancy. Although no direct evidence of oxidative stress and inflammatory response was observed in severe pre-eclampsia, a reduction of gamma-tocopherol suggests the possible precedence of oxidative stress in this condition. Higher levels of isoprostanes and prostaglandin metabolite in late pregnancy suggest the importance of both free radicals and cyclooxygenase-catalysed oxidation products in normal biological processes of pregnancy.     

Oxidative stress and 8-iso-prostaglandin F(2alpha) induce ectodomain shedding of CD163 and release of tumor necrosis factor-alpha from human monocytes

CD163 is a membrane glycoprotein of the cysteine-rich scavenger receptor superfamily. Upon an inflammatory stimulus CD163 undergoes ectodomain shedding and the soluble protein has been shown to play a role in downregulation of inflammation. The purpose of the present study was to identify a physiological activator of CD163 shedding that is consistently present under inflammatory conditions. Therefore, we elucidated whether oxidative stress or 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) is involved in shedding of CD163. Oxidative stress induced by H(2)O(2) or a NO donor as well as 8-iso-PGF(2alpha) induced significant shedding of CD163. In contrast, release of CD163 was not stimulated by PGF(2alpha). We identified both calcium and reactive oxygen species as common cellular mediators of CD163 release. Since shedding of both CD163 and tumor necrosis factor-alpha (TNFalpha) is known to be mediated by a TIMP-3-sensitive metalloproteinase we examined whether release of TNFalpha was induced by the same mediators that trigger shedding of CD163. Only oxidative stress generated by H(2)O(2) as well as 8-iso-PGF(2alpha) and PGF(2alpha) enhanced TNFalpha secretion. Thus, we identified novel common and divergent activators of shedding of CD163 and TNFalpha. These inducers of shedding are present in inflammation and might play an important role in membrane protein cleavage.     

Assessment of heterogeneous airway constriction in dogs: a structure-function analysis

Obstructive lung diseases are often characterized by heterogeneous patterns of bronchoconstriction, although specific relationships between structural heterogeneity and lung function have yet to be established. We measured respiratory input impedance (Zrs) in eight anesthetized dogs using broadband forced oscillations at baseline and during intravenous methacholine (MCh) infusion. We also obtained high-resolution computed tomographic (HRCT) scans in 4 dogs and identified 20-30 individual airway segments in each animal. The Zrs spectra and HRCT images were obtained before and 5 min following a deep inspiration (DI) to 35 cmH(2)O. Each Zrs spectrum was fitted with two different models of the respiratory system: 1) a lumped airways model consisting of a single airway compartment, and 2) a distributed airways model incorporating a continuous distribution of airway resistances. For the latter, we found that the mean level and spread of airway resistances increased with MCh dose. Whereas a DI had no effect on average airway resistance during MCh infusion, it did increase the level of airway heterogeneity. At baseline and low-to-moderate doses of MCh, the lumped airways model was statistically more appropriate to describe Zrs in the majority of dogs. At the highest doses of MCh, the distributed airways model provided a superior fit in half of the dogs. There was a significant correlation between heterogeneity assessed with inverse modeling and the standard deviation of airway diameters obtained from HRCT. These data demonstrate that increases in airway heterogeneity as assessed with forced oscillations and inverse modeling can be linked to specific structural alterations in airway diameters.     

Prostaglandin F2alpha involves heparan sulphate sugar chains and FGFRs to modulate osteoblast growth and differentiation

The present investigation extends our previous studies on PGF2alpha-mediated signalling in osteoblast metabolism. In particular, the role of PGF2alpha as modulator of heparan sulphate proteoglycans (HSPGs), fibroblast growth factor 2 (FGF-2) and fibroblast growth factor receptors (FGFRs) was evaluated. We hereby reported the novel observation that PGF2alpha was able to promote the formation of HSPGs/FGF-2/FGFRs complexes. Moreover, our data suggested that PGF2alpha could induce new synthesis of heparan sulphate (HS) chains on osteoblasts by a mechanism involving a modulation of MAPK signalling and that HS is required for the regulation of FGF-2 induced by PGF2alpha. Indeed, a proteolytic cleavage of HSPGs with heparinase III (Hep III) prior to PGF2alpha administration down-regulated the basal expression of phospho-p44/42, likely inhibiting FGFRs tyrosine kinase activity. Interestingly, MAPK signalling influenced syntheses and subcellular localization of FGF-2, its specific receptor and HS. In addition, the proteolytic cleavage by Hep III and the MAPK kinase inhibition by PD-98059 also revealed that PGF2alpha induced cell proliferation is dependent on HSPGs and FGF-2 specific receptor, respectively. Of further relevance of this study, we demonstrated, by using a specific siRNA for FGFR1, that PGF2alpha modulates Runx2 expression by FGFR1 and HS.     

A comparison of the contractile activity of PGD2 and PGF2 alpha on human isolated bronchus

Prostaglandins may be implicated in the bronchoconstriction which occurs in asthma. Prostaglandins F2 alpha (PGF2 alpha) and D2 (PGD2) have been reported to produce bronchoconstriction in asthmatic subjects in vivo and PGF2 alpha contracts human isolated airway smooth muscle. We examined the relative efficacy and potency of PGF2 alpha and PGD2 on human bronchial spiral strips taken from 6 patients at thoracotomy. PGF2 alpha had greater efficacy than PGD2. The mean % Tmax (percentage of maximal contractile response) +/- s.e. mean were 84 +/- 7 and 54 +/- 7 respectively (P less than 0.05). PGF2 alpha (mean pD2 +/- s.e. mean = 6.39 +/- 0.6) tended to be more potent than PGD2 (5.68 +/- 0.2). Since, in vivo, PGD2 has greater efficacy and potency than PGF2 alpha, our results suggest that the in vivo effect of these prostaglandins does not result solely from an action on airway muscle.     

Blood-brain barrier damage induces release of alpha2-macroglobulin

Blood-brain barrier (BBB) failure occurs in many neurological diseases and is caused in part by activation of proinflammatory factors including matrix metalloproteinases. Counterbalancing, "BBB protective" cascades have recently been described, including NO-mediated interleukin 6 release by glia. Interleukin 6 has been shown to trigger production of matrix metalloproteinase inhibitors such as alpha2-macroglobulin (alpha2M). We hypothesized that BBB failure may result in increased alpha(2)M release by perivascular astrocytes. This was initially tested in patients undergoing iatrogenic BBB disruption by hyperosmotic mannitol for intra-arterial chemotherapy of brain tumors. Serum samples revealed significantly increased levels of alpha2M at 4 h after BBB disruption by hyperosmotic mannitol. In parallel in vitro experiments, we observed a similar increase of alpha2M release by astrocytes under conditions mimicking BBB failure and perivascular edema. For both experiments, protein analysis was initially performed by bidimensional gel electrophoresis and mass spectrometry followed by Western blotting immunodetection. We conclude that, in addition to proinflammatory changes, BBB failure may also trigger protective release of alpha2M by perivascular astrocytes as well as peripheral source.     

Secretion of PGF2alpha and oxytocin during hyperthermia in cyclic and pregnant heifers

The effects of acute heat stress (HS) and oxytocin (OT) injection on plasma concentrations of PGF2alpha and OT were examined in cyclic (C; n = 15) and pregnant (P; n = 11) dairy heifers. On Day 17 of synchronized estrous cycles, animals were randomly assigned to either thermoneutral (TN; 20 degrees C, 20% RH) or HS (42 degrees C, 60% RH) chambers. The jugular vein of each heifer was cannulated and blood samples collected hourly for 4 h, then every 15 min for an additional 3 h. Oxytocin (100 IU) was injected (IV) 5 h after the start of blood collection. Plasma samples were assayed subsequently for concentrations of 13,14-dihydro-15-keto PGF2alpha (PGFM) and OT. During the 7-h experiment, body temperature of HS heifers reached 41.2 degrees C as compared to 38.5 degrees C in control heifers. Plasma concentrations of PGFM increased (P<0.05) and peaked 30 min after OT injection in C (890 pg/ml) and P (540 pg/ml) heifers. In C heifers, heat stress failed to alter PGFM concentrations either before or after OT injection. In the P group, PGFM concentrations following OT injection tended to be higher in HS heifers were further TN heifers (peak values of 690 vs. 410 pg/ml). Pregnant TN and HS heifers were further classified as responders or non-responders to OT challenge according to a cutoff value for PGFM of 193 pg/ml (overall mean of C heifers minus 1 SD). Five of six HS and one of five TN pregnant heifers were classified as responders (P<0.06). Oxytocin concentrations in plasma prior to injection of exogenous OT were not affected by HS or pregnancy status. It is concluded that in C heifers, acute HS in vivo does not cause any further rise in PGF2alpha secretion. However, in P heifers, HS appears to antagonize suppressive effects of the embryo on uterine secretion of PGF2alpha, as indicated by the larger proportion of P heifers responding to OT challenge.     

Salivary isoprostanes indicate increased oxidation injury in periodontitis with additional tobacco abuse

Isoprostanes (IPs) are indicators of in-vivo oxidative stress, and have been successfully used as markers for chronic inflammatory processes. The presence of chronic periodontal disease and cigarette smoking has been individually linked to the development of atherosclerosis, yet data regarding oxidative stress in this context are not available yet. The aim of this study was to evaluate levels of the salivary prostaglandins (PGs) 8-epi-PGF(2alpha), 6-oxo-PGF(1alpha), thromboxane B(2) (TXB(2)) and PGF(2alpha) in association with periodontal disease status with and without additional cigarette smoking. We analyzed saliva samples from 121 adults, (aged 21-73 years, 90 non-smokers, 31 smokers) for levels of 8-epi-PGF(2alpha), 6-oxo-PGF(1alpha), TXB(2) and PGF(2alpha). On the basis of periodontal disease indices the periodontal status of each subject was assessed and outcomes were then correlated with smoking status and laboratory findings. Salivary 8-epi-PGF(2alpha) levels increased with deteriorating plaque index, and were significantly higher (115.5 +/- 23.5 pg/ml) in smoking individuals, when compared to non-smokers (70.2 +/- 20.4 pg/ml, p<0.0001). In addition, smokers showed higher TXB(2) and PGF(2alphas) and lower 6-oxo-PGF(1alpha) levels p<0.0001). Oxidative stress, as reflected by elevated salivary 8-epi-PGF(2alpha) levels, is associated with the extent of periodontal disease and is significantly aggravated by concomitant tobacco abuse. Chronic inflammation and smoking have been individually associated with the development of atherosclerosis. The results of this study indicate that: 1) salivary IPs can reliably assess the degree of oxidative stress, and: 2) smoking and periodontal disease are two modifiable cardiovascular risk factors, able to potentiate each other.