Active smoking and a history of smoking are associated with enhanced prostaglandin F2α, interleukin-6 and F2-isoprostane formation in elderly men

doi:10.1016/j.atherosclerosis.2004.11.026

Atherosclerosis

Volume 181, Issue 1, July 2005, Pages 201-207

https://doi.org/10.1016/j.atherosclerosis.2004.11.026 Get rights and content

Abstract

The underlying mechanisms by which smoking induces cardiovascular diseases are largely unknown. The effect of smoking status on the cyclooxygenase (COX)-mediated inflammatory indicator prostaglandin F_2α (PGF_2α) has never been studied. Associations of cytokines and antioxidants and smoking status, have shown conflicting results. Urinary 15-keto-dihydro-PGF_2α (a major metabolite of PGF_2α), serum interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP), serum amyloid protein A (SAA), urinary 8-iso-PGF_2α (an F₂-isoprostane, indicator of oxidative stress), and serum α-tocopherol were quantified in a population-based sample (n = 642) of 77-year old men without diabetes. Fifty-five men were current smokers and 391 former smokers. Inflammatory indicators were increased in current smokers (15-keto-dihydro-PGF_2α, P < 0.001; IL-6, P = 0.01) than non-smokers. 8-iso-PGF_2α was increased (P < 0.01) and α-tocopherol reduced (P < 0.001) in current smokers. Further, former smokers had increased formation of 15-keto-dihydro-PGF_2α, IL-6 and 8-iso-PGF_2α compared non-smokers. This is the first study to show that smokers have increased PGF_2α formation, thus enhanced COX-mediated inflammation, in addition to elevated levels of cytokines and isoprostanes. Subclinical COX- and cytokine-mediated inflammation and oxidative stress are ongoing processes not only in active smokers but also in former smokers which may contribute to the accelerated atherosclerosis associated with smoking.

Introduction

Cigarette smoking is common worldwide and is believed to be associated with accelerating atherosclerosis and development of cardiovascular diseases [1]. The underlying mechanisms by which smoking induces cardiovascular diseases are still largely unknown. Chronic low-grade inflammation is a contributing factor in the pathogenesis of atherosclerosis [2], [3]. Inflammatory processes can be studied by quantification of cyclooxygenase (COX)-induced or cytokine-mediated products [4]. Prostaglandins and thromboxanes are derived from arachidonic acid and COX catalyses their formation. These prostanoids are important mediators of the inflammatory process [5], [6]. Prostaglandin F_2α (PGF_2α) is one of the major prostaglandins formed at sites of inflammation [7], [8]. PGF_2α formation in vivo is preferably quantified by measurement of 15-keto-dihydro-PGF_2α [9], which is a major metabolite of PGF_2α in plasma. 15-Keto-dihydro-PGF_2α has been shown to be a potent indicator of PGF_2α formation and COX-mediated inflammatory processes in vivo [10], [11], [12]. Due to methodological difficulties with the quantification of PGF_2α earlier, little is known about the role of PGF_2α in atherogenesis until now. A recent study showed an association between type 2 diabetes and PGF_2α, thus, emerging a possible role of PGF_2α in atherogenesis [4]. The effect of smoking on interleukin-6 (IL-6), and cytokine-mediated products (C-reactive protein (CRP), serum amyloid protein A (SAA)) have been studied, but the effect of former smoking status on cytokine-mediated inflammation is not fully known.

Oxidative stress is another possible contributor to atherogenesis [13]. F₂-isoprostanes, isomers of PGF_2α, are formed during free-radical catalysed, non-enzymatic peroxidation of arachidonic acid [14]. 8-iso-PGF_2α, a major F₂-isoprostane, is a reliable indicator of oxidative stress in vivo and has been associated with several risk factors for atherosclerosis including: diabetes, obesity and hypercholesterolemia as recently reviewed [15]. Several studies have reported an increased level of 8-iso-PGF_2α formation in smokers including [16], [17]. Studies of serum antioxidants in smokers have shown conflicting results [18].

The aim of this study was to investigate the effect of long-term smoking and former smoking on PGF_2α as an indicator of COX-mediated inflammation (15-keto-dihydro-PGF_2α), cytokine-mediated inflammation (IL-6, high sensitivity C-reactive protein (hsCRP), SAA), and indicators of oxidative stress (8-iso-PGF_2α, tocopherols) in a population-based cross-sectional study with sex, age and ethnicity matched non-smokers as controls.

Section snippets

Study cohort

The subjects in this study were participants in the re-investigation of the Uppsala Longitudinal Study of Adult Men (ULSAM)-cohort at 77 years of age, described in detail previously [4]. Briefly, this Swedish population-based cohort originally started in 1970, when all men born 1920–1924 and living in Uppsala, were invited to a health screening (2841 men invited, participation rate 82%). The cohort men were invited to re-investigations at age 60 and 70, as described previously [19]. In this

Results

Metabolic characteristics, medical history and medication for non-smokers, former and current smokers are summarized in Table 1. BMI was significantly lower in the group of current smokers. Other metabolic variables, medical history and medication did not differ in non-smokers, former and current smokers.

Discussion

Prostaglandins are COX-mediated bioactive products which are involved in inflammatory processes [6]. Quantification of PGF_2α in plasma or urine is not reliable because PGF_2α in plasma has a short half-life of less than 1 min and could easily be formed as an artefact during blood sampling [9]. A major metabolite of PGF_2αin plasma, 15-keto-dihydro-PGF_2α, is stable and not formed as an artefact [9], and has been widely been used as a biomarker of PGF_2α.

PGF_2α formation, as measured by

Acknowledgements

This study was financially supported by Swedish Heart–Lung Foundation, Swedish Society of Medicine and Thuréus Foundation. We are grateful to Barbro Simu, Siv Tengblad and Eva Sejby for technical assistance.

References (38)

S. Basu
Radioimmunoassay of 15-keto-13,14-dihydro-prostaglandin F2alpha: an index for inflammation via cyclooxygenase catalysed lipid peroxidation
Prostaglandins Leukot Essent Fatty Acids
(1998)
S. Basu et al.
Oxidative injury and survival during endotoxemia
FEBS Lett
(1998)
S. Basu et al.
Development of a novel biomarker of free radical damage in reperfusion injury after cardiac arrest
FEBS Lett
(2000)
S. Basu
Radioimmunoassay of 8-iso-prostaglandin F2alpha: an index for oxidative injury via free radical catalysed lipid peroxidation
Prostaglandins Leukot Essent Fatty Acids
(1998)
S. Fischer et al.
Formation of prostacyclin and thromboxane in man as measured by the main urinary metabolites
Biochim Biophys Acta
(1986)
S.E. Barrow et al.
Cigarette smoking: profiles of thromboxane- and prostacyclin-derived products in human urine
Biochim Biophys Acta
(1989)
I. Das
Raised C-reactive protein levels in serum from smokers
Clin Chim Acta
(1985)
K.M. Brown et al.
Vitamin E supplementation suppresses indexes of lipid peroxidation and platelet counts in blood of smokers and nonsmokers but plasma lipoprotein concentrations remain unchanged
Am J Clin Nutr
(1994)
M.G. Traber et al.
Vitamin E kinetics in smokers and nonsmokers
Free Radic Biol Med
(2001)
H. Pilz et al.
Quitting cigarette smoking results in a fast improvement of in vivo oxidation injury (determined via plasma, serum and urinary isoprostane)
Thromb Res
(2000)

F. Chehne et al.

Effect of giving up cigarette smoking and restarting in patients with clinically manifested atherosclerosis

Prostaglandins Leukot Essent Fatty Acids

(2002)

I.S. Ockene et al.

Cigarette smoking, cardiovascular disease, and stroke: a statement for healthcare professionals from the American Heart Association. American Heart Association Task Force on Risk Reduction

Circulation

(1997)

P.M. Ridker et al.

Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men

N Engl J Med

(1997)

J. Danesh et al.

Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses

BMJ

(2000)

J. Helmersson et al.

Association of type 2 diabetes with cyclooxygenase-mediated inflammation and oxidative stress in an elderly population

Circulation

(2004)

S. Bergström

Prostaglandins: members of a new hormonal system. These physiologically very potent compounds of ubiquitous occurrence are formed from essential fatty acids

Science

(1967)

J.R. Vane

Prostaglandins as mediators of inflammation

Adv Prostaglandin Thromboxane Res

(1976)

D.A. Willoughby

Heberden Oration, 1974. Human arthritis applied to animal models. Towards a better therapy

Ann Rheum Dis

(1975)

D.K. Mutschler et al.

Microdialysis-evaluated myocardial cyclooxygenase-mediated inflammation and early circulatory depression in porcine endotoxemia

Crit Care Med

(2003)

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Clinical ResearchActive smoking and a history of smoking are associated with enhanced prostaglandin F2α, interleukin-6 and F2-isoprostane formation in elderly men

Abstract

Introduction

Section snippets

Study cohort

Results

Discussion

Acknowledgements

Prostaglandins Leukot Essent Fatty Acids

FEBS Lett

FEBS Lett

Prostaglandins Leukot Essent Fatty Acids

Biochim Biophys Acta

Biochim Biophys Acta

Clin Chim Acta

Am J Clin Nutr

Free Radic Biol Med

Thromb Res

Prostaglandins Leukot Essent Fatty Acids

Cigarette smoking, cardiovascular disease, and stroke: a statement for healthcare professionals from the American Heart Association. American Heart Association Task Force on Risk Reduction

Circulation

Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men

N Engl J Med

Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses

BMJ

Association of type 2 diabetes with cyclooxygenase-mediated inflammation and oxidative stress in an elderly population

Circulation

Prostaglandins: members of a new hormonal system. These physiologically very potent compounds of ubiquitous occurrence are formed from essential fatty acids

Science

Prostaglandins as mediators of inflammation

Adv Prostaglandin Thromboxane Res

Heberden Oration, 1974. Human arthritis applied to animal models. Towards a better therapy

Ann Rheum Dis

Microdialysis-evaluated myocardial cyclooxygenase-mediated inflammation and early circulatory depression in porcine endotoxemia

Crit Care Med

Clinical Research
Active smoking and a history of smoking are associated with enhanced prostaglandin F_2α, interleukin-6 and F₂-isoprostane formation in elderly men