Content uploaded by Asha Ramesh
Author content
All content in this area was uploaded by Asha Ramesh on Dec 30, 2017
Content may be subject to copyright.
Review
Chronic obstructive pulmonary disease and periodontitis –unwinding
their linking mechanisms
Asha Ramesh
n
, Sheeja S. Varghese
1
, N.D. Jayakumar
2
, Sankari Malaiappan
3
Department of Periodontics, Saveetha Dental College and Hospital, No. 162, Poonamallee High Road, Velappanchavadi 600077, Chennai, India
article info
Article history:
Received 25 August 2015
Received in revised form
11 September 2015
Accepted 15 September 2015
Available online 3 October 2015
Keywords:
Periodontitis
COPD
Neutrophil
Oxidative stress
Association
abstract
Background: Chronic obstructive pulmonary disease (COPD) and periodontitis are severe debilitating
disorders of inflammatory origin. COPD manifests as inflammation of the lung connective tissue caused
by irritants such as smoking and dust particles, resulting in narrowing of the airway. Periodontitis follows
the same inflammatory course with the resultant destruction of the local connective tissue, and several
irritants are well-documented risk factors for this disease.
Highlights: Neutrophilic dominance is well established in both of these conditions, and some evidence
suggests that periodontopathogens play a role in causing respiratory infections. Given the similarities in
the etiopathogenesis and the risk factor profiles of these diseases, a common foundation exists to suggest
an inter relationship between the two diseases.
Conclusion: The present article briefly reviews the interlinking mechanisms between the two diseases,
starting with the role of periodontal pathogens, innate immunity, and, ultimately, imbalances in oxi-
dative stress and the protease–antiprotease system. Although epidemiological evidence provides no clear
association between these two diseases, the striking commonalities should not be overlooked. Hence,
future research should be targeted to this area in order to obtain constructive information.
&2015 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2. Role of periodontal pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.1. Neutrophilic predominance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.2. Neutrophil extracellular traps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.3. Protease/anti-protease imbalance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.4. Oxidative stress in the midst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Ethical approval. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
References.............................................................................................................. 26
1. Introduction
Periodontitis is a chronic inflammatory disease that results in the
destruction of the supporting structures of the teeth. The etiology is
multifactorial, with periodontopathogens being the major crux in the
initiation and progression of the disease. Plaque build-up allows the
growth of anaerobic bacteria [1], which eventually leads to the
recruitment and activation of neutrophils. This results in the up-
regulation of pro-inflammatory cytokines, leading to the release of
neutrophilic enzymes to combat the invaders. Prolonged exposure of
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/job
Journal of Oral Biosciences
http://dx.doi.org/10.1016/j.job.2015.09.001
1349-0079/&2015 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.
Abbreviations: COPD, Chronic obstructive pulmonary disease; Fmlp, N-formyl-
Met-Leu-Phe; NET, Neutrophil extracellular traps; GCF, Gingival crevicular fluid;
MMP, Matrix metalloproteinase
n
Corresponding author. Tel.: þ91 9841722113.
E-mail addresses: ash.periopg@gmail.com (A. Ramesh),
drsheeja@rediffmail.com (S.S. Varghese),
principaldental@saveetha.com (N.D. Jayakumar),
msankari@gmail.com (S. Malaiappan).
1
Tel.: 9884042252.
2
Tel.: 9444071930.
3
Tel.: 9840285905.
Journal of Oral Biosciences 58 (2016) 23–26
the connective tissue to these insults results in its degradation and the
subsequent loss of ligamentous support and alveolar bone, eventually
leading to tooth loss [2].
The focal infection theory proposed by William Hunter in the
1800s suggested that the oral cavity was the root cause of all sys-
temic diseases; however, this theory was widely disregarded in the
1930s. This theory has been revisited in the modern era because of
the multitude of systemic influences exerted by periodontal infec-
tions, which are a current focus of research [3]. Recent evidence has
established that periodontitis could be a probable risk factor for
cardiovascular diseases such as atherosclerosis, stroke, myocardial
infarction, diabetes, adverse pregnancy outcome, and respiratory
disorders. This paradoxical shift has been studied extensively and is
now termed “periodontal medicine”.
Respiratory disorders rank high in the leading causes of mor-
tality and morbidity globally, with upper respiratory infections
affecting over 2 billion people and chronic respiratory infections
causing an increase in years lived with disability (YLD) [4]. Chronic
obstructive pulmonary disease (COPD) is a generic term that is
defined by the chronic obstruction of airflow. The pathological
subtypes include emphysema, chronic bronchitis, and small airways
disease; although these are distinct entities, they can occur together
in a single patient. This is also a predominantly neutrophil-
mediated inflammatory disease, and an increased number of neu-
trophils has been reported in the airways of patients with COPD [5].
Periodontitis and COPD share a common risk factor profile,
with both diseases showing increased susceptibility of the host to
environmental and genetic factors. Both of these diseases are
bacterial in origin, with a neutrophilic predominance, and they
manifest as chronic inflammation with underlying connective
tissue destruction of the respective areas. Further, an imbalance is
present in the redox system and in protease–antiprotease activity,
which are prime targets in the pathogenesis of the two diseases.
Several epidemiological studies have attempted to find an asso-
ciation between the two diseases [6,7]. A randomized clinical trial
showed that non-surgical periodontal therapy improved lung
function in COPD patients with chronic periodontitis [8]. In addi-
tion, a recent meta-analysis by Zeng et al. of 14 observational
studies showed that populations with periodontal disease had an
overall increased risk of developing COPD (odds ratio, 2.40); these
authors concluded that periodontal disease significantly increased
the risk of COPD, but the mechanisms remain unclear [9]. Since the
oral cavity physically continues into the respiratory tract, and
because these two diseases share innumerable contributory
mechanisms, elucidating the connecting links is necessary in order
to deduce the association between these two chronic diseases.
This review will focus on the role of periodontal pathogens and
various other mechanisms through which these conditions are
inter-connected.
2. Role of periodontal pathogens
Scannapieco elucidated various mechanisms by which oral
bacteria can contribute to the pathogenesis of respiratory infec-
tions [10]:
1. The aspiration of oral pathogens, such as Porphyromonas gingi-
valis (P. gingivalis), Aggregatibacter actinomycetemcomitans (A.
actinomycetemcomitans), etc., into the lung can cause infection.
2. Periodontal disease-associated enzymes in saliva may modify
the mucosal surfaces to promote adhesion and colonization by
respiratory pathogens, which are then aspirated into the lung.
3. Periodontal disease-associated enzymes may destroy salivary
pellicles on pathogenic bacteria to hinder their clearance from
the mucosal surface.
4. Cytokines originating from the periodontal tissues may alter the
respiratory epithelium to promote infection by respiratory
pathogens.
Laboratory studies have suggested that oral anaerobes such as
P. gingivalis can cause marked inflammation when instilled into
the lungs of laboratory animals [11]. Further, the colonization of
the Prevotella species (a periodontopathogen) in patients may be
associated with an infectious process leading to ventilator-
associated pneumonia and a systemic humoral response [12].
As previously mentioned, oral bacteria can modulate the adhe-
sion of respiratory pathogens on epithelial cell lines. Oral bacterial
products or cytokines in the oral/pharyngeal aspirate may stimulate
cytokine production from respiratory epithelial cells, resulting in
the recruitment of inflammatory cells. The resulting inflamed epi-
thelium may be more prone to respiratory infection. A study by
Scannapieco et al showed that A. actinomycetemcomitans was the
stronger stimulant in the production of pro-inflammatory cytokines
from epithelial cells when compared with P. gingivalis [13].A. acti-
nomycetemcomitans has been established as the most prominent
pathogen in human periodontal disease [14].
2.1. Neutrophilic predominance
Although many immune cells like macrophages and dendritic
cells have been proposed to play a role in the pathogenesis of
periodontitis and COPD, neutrophils are considered the most
important because of their high preponderance in both diseases.
Neutrophil counts are high in COPD, and this does not correlate
with effective elimination of the microbes. This results in collateral
lung tissue damage due to the release of enzymes and reactive
oxygen species (ROS). The amount of neutrophil elastase present
in the lung tissue has been correlated with the severity of
emphysema [15]. Further, neutrophilic function is impaired in
COPD patients. A previous study reported that neutrophils isolated
from the blood of individuals with moderate-to-severe COPD
showed decreased chemotaxis in response to classical chemoat-
tractants such as bacterial protein N-formyl-Met-Leu-Phe (fMLP)
and the pro-inflammatory cytokine interleukin (IL)-8, with a cor-
relation between the reduced chemotaxis of neutrophils to fMLP
and the degree of airflow limitation [16]. Moreover, neutrophils
from individuals with COPD migrate faster than those from heal-
thy subjects, but the accuracy of migration toward known che-
moattractants, such as fMLP and IL-8, is markedly reduced [17].
Cigarette smoke, which is an exogenous source of oxidants, free
radicals, and neutrophils have been shown to induce oxidative
stress in the lung tissue of COPD patients.
The role of neutrophils in periodontitis has not been clearly
elucidated since both qualitative and quantitative differences
have been observed. Neutrophil function shows both hyper and
hypo activity in response to bacterial stimuli in various forms of
periodontitis. Evidence suggests that neutrophil defects generally
lead to a predisposition for aggressive forms of periodontitis and
hyperactivity or that elevated function is associated with an
increased respiratory burst of the neutrophils [18]. Thus, under-
standing the role of neutrophils in periodontitis and COPD is
necessary to ascertain the common pathophysiological pathway
between these two diseases.
2.2. Neutrophil extracellular traps
Neutrophil extracellular traps (NETs) are web-like extracellular
structures of decondensed chromatin associated with histones and
enzymes such as neutrophil elastase (NE) and myeloperoxidase
(MPO), which are both antimicrobial and cytotoxic. They are
released by activated neutrophils, mainly during a distinct process
A. Ramesh et al. / Journal of Oral Biosciences 58 (2016) 23–2624
of cell death termed NETosis [19]. The triggers of NETosis are the
bacterial cell wall components that activate complement recep-
tors, Fc receptors, or toll-like receptors on neutrophil surfaces [20].
Once in the extracellular space, these components have the ability
to trap micro-organisms and to expose them to high local con-
centrations of degradative enzymes [21]. This is a type of adaptive
mechanism, wherein the bacterial elimination occurs even after
the death of the neutrophil. These mechanisms form an important
part of innate immunity and they are associated with the release
of ROS and degradative enzymes that play a crucial role in bacteria
elimination and the concomitant tissue damage in chronic dis-
eases like periodontitis and COPD.
A study performed by using the sputa of patients with both the
stable and exacerbated forms of COPD showed that this is char-
acterized by the presence of large amounts of NETs and NET-
forming neutrophils [22]. In addition, studies have shown that an
abundance of NETs contain trapped bacteria in the periodontal
pocket (pocket surface, gingival crevicular fluid [GCF], and pus)
[23–25]. The knowledge that NETs are involved in both diseases
invokes the possibility of developing new therapeutic strategies
that target the host immune defense mechanisms.
2.3. Protease/anti-protease imbalance
Neutrophils are the prime source of proteolytic enzymes such as
matrix metalloproteinase (MMP) and elastase. The neutrophil elastase
present in the azurophilic granules has been shown to play a pivotal
role in the pathogenesis of COPD. This hypothesis was proposed in the
1960s, when patients with deficiency of
α
1
-antitrypsin (AAT) were
noted to be specifically susceptible to the development of early onset
emphysema, disproportionate to smoking history [26].AATwaslater
foundtohaveaninhibitoryactiononneutrophilelastase.Insupportof
this mechanism, a relationship between the elastase and anti-elastase
imbalance and the extent of emphysema was evident in the broncho–
alveolar lavage fluid from patients with COPD [27]. This tilt in the
balance in favor of proteases is associated with connective tissue
destruction, in which components like collagen, laminin, and elastin
are targeted by neutrophil elastase.
MMPs are endogenous enzymes with proteolytic activity
against all components of the extracellular matrix and basement
membrane, leading to subsequent periodontal destruction.
Pathogens in microbial dental plaque are capable of stimulating
host cells to increase MMP release, which is considered one of the
indirect mechanisms of tissue destruction observed in period-
ontitis [28]. Vernooy et al. reported increased MMP-8 and MMP-9
activity in the airway compartment of patients with mild-to-
moderate COPD and suggested that an impaired proteinase-
antiprotease balance exists in COPD [29].
Since all of these enzymes comprise the host response compo-
nent in the pathogenesis of these diseases, therapeutic strategies
such as host modulation have been implemented. For periodontitis,
the FDA has approved the use of the host modulatory agent Periostat
(a sub antimicrobial dose of doxycycline) in conjunction with non-
surgical periodontal therapy. In a landmark study by Canton et al, the
usage of a sub antimicrobial dose of doxycycline in conjunction with
scaling and root planing resulted in a significant improvement in
clinical parameters like probing depth and the clinical attachment
level in adult periodontitis patients [30].Thelong-termuseofmac-
rolides such as azithromycin was shown to reduce the risk of acute
exacerbations in patients with COPD. This was highlighted in a study
where 1142 patients at an increased risk of COPD exacerbation were
randomly assigned at a 1:1 ratio to receive azithromycin (n¼570) at
a dose of 250 mg daily or placebo (n¼572) for 1 year in addition to
their usual care [31]. The median time to acute COPD exacerbation
was 266 days in the azithromycin group compared with 174 days in
the placebo group.
2.4. Oxidative stress in the midst
Excessive production of free radicals and ROS occurs when oxida-
tive stress increases. The lungs are the site of the majority of redox
reactions with exposure to free radicals derived from tobacco smoke
and air pollution [32]. Immune cells such as macrophages and neu-
trophils are endogenous producers of free radicals, which are released
because of bacterial stimulation or environmental insults [33].ROS
may damage the tissues of the body, depending on the amount and
duration of exposure, and may further act as triggers for enzymatically
generated ROS released from respiratory, immune, and inflammatory
cells. The body is equipped with antioxidant defense mechanisms
with enzymes such as superoxide dismutase, glutathione peroxidase,
catalase, and peroxiredoxins. These antioxidants function by degrading
the free radicals and ROS and nullifying their harmful effects.
A positive relationship exists between sputum neutrophils and
hydrogen peroxide levels in patients with severe COPD, suggesting
that these cells are the major source of oxidants [34]. Further,
neutrophils from COPD patients were shown to have greater oxi-
dant production than those of smokers with normal lung function
and non-smoking control individuals [35]. The levels of protective
antioxidants are significantly depleted in the alveolar macro-
phages of COPD patients, and recent studies indicate that anti-
oxidative mechanisms are not sufficiently adapted in inflamma-
tory respiratory diseases such as COPD; therefore, the oxidants
may subsequently take on the leading role under these conditions.
Polymorphonuclear neutrophils (PMNs) have an established role in
periodontitis, but whether their hyperactivity is responsible for period-
ontal destruction remains a controversial topic. This is because neu-
trophil defects have been associated with localized aggressive period-
ontitis, which is a more rampant and severe form of the disease;
therefore, the pathogenic mechanism remains to be elucidated. Never-
theless, oxidative stress markers have been routinely studied in period-
ontal research. In chronic periodontitis, even unstimulated neutrophils
had greater spontaneous ROS production, as detected by chemilumi-
nescence, than cells from control individuals [36].Anotherstudyshowed
that antioxidant enzymes like superoxide dismutase, catalase, and glu-
tathione reductase are significantly lower in chronic periodontitis sub-
jects when compared to healthy controls [37]. Thus, cumulative evidence
suggests that oxidative stress plays a major role in both diseases.
3. Conclusion
Since these two diseases have many features in common, i.e., they
follow the same inflammatory course with the resultant destruction
of the local connective tissue, it is reasonable to suppose that a
holistic treatment approach is required to combat these two condi-
tions. Neutrophils, with their oxidants and proteases, play a pre-
dominant role in the pathogenesis of both disorders. The future
scope of research should be targeted towards finding the triggers
that cause the imbalance within neutrophils and initiate the disease
process. Although current epidemiologic studies have provided little
evidence to support an association between these two diseases, the
striking similarities in the disease processes suggest that such a
relationship exists. Clinical trials analyzing the causality and patho-
logical basis of these diseases are a necessity.
Ethical approval
Ethical approval was not obtained since this is a review article.
Conflict of interest
None.
A. Ramesh et al. / Journal of Oral Biosciences 58 (2016) 23–26 25
Acknowledgments
The authors wish to thank the staff and students of the
Department of Periodontics, Saveetha Dental College, for their
assistance with this manuscript.
References
[1] Listgarten MA. Pathogenesis of periodontitis. J Clin Periodontol 1986;13:418–30.
[2] Laine ML, Crielaard W, Loos BG. Genetic susceptibility to periodontitis. Periodontol
2000 2012;58:37–68.
[3] Hunter W. The coming of age of oral sepsis. Br Med J 1921;1:859.
[4] Global Burden of Disease Study 2013 Collaborators. Global, regional, and
national incidence, prevalence, and years lived with disability for 301 acute
and chronic diseases and injuries in 188 countries, 1990-2013: a systematic
analysis for the Global Burden of Disease Study 2013. Lancet 2015;386:743–
800.
[5] Confalonieri M, Mainardi E, Della PR, Bernorio S, Gandola L, Beghe B, Spane-
vello A. Inhaled corticosteroids reduce neutrophil bronchial inflammation in
patients with chronic obstructive pulmonary disease. Thorax 1998;53:583–5.
[6] Wang Z, Zhou X, Zhang J, Zhang L, Song Y, Hu FB, Wang C. Periodontal health,
oral health behaviours, and chronic obstructive pulmonary disease. J Clin Per-
iodontol 2009;36:750–5.
[7] Liu Z, Zhang W, Zhang J, Zhou X, Zhang L, Song Y, Wang Z. Oral hygiene, per-
iodontal health and chronic obstructive pulmonary disease exacerbations. J Clin
Periodontol 2012;39:45–52.
[8] Zhou X, Han J, Liu Z, Song Y, Wang Z, Sun Z. Effects of periodontal treatment on
lung function and exacerbation frequency in patients with chronic obstructive
pulmonary disease and chronic periodontitis: a 2-year pilot randomized
controlled trial. J Clin Periodontol 2014;41:564–72.
[9] Zeng XT, Tu ML, Liu DY, Zheng D, Zhang J, Leng W. Periodontal disease and risk of
chronic obstructive pulmonary disease: a meta-analysis of observational studies.
PLoS One 2012;7:e46508.
[10] Scannapieco FA, Mylotte JM. Relationships between periodontal disease and
bacterial pneumonia. J Periodontol 1996;67:S1114–22.
[11] Nelson S, Laughon BE, Summer WR, Eckhaus MA, Bartlett JG, Jakab GJ. Char-
acterization of the pulmonary inflammatory response to an anaerobic bac-
terial challenge. Am Rev Respir Dis 1986;133:212–7.
[12] Grollier G, Doré P, Robert R, Ingrand P, Gréjon C, Fauchere JL. Antibody
response to Prevotella spp. in patients with ventilator-associated pneumonia.
Clin Diagn Lab Immunol 1996;3:61–5.
[13] Scannapieco FA, Wang B, Shiau HJ. Oral bacteria and respiratory infection:
effects on respiratory pathogen adhesion and epithelial cell proinflammatory
cytokine production. Ann Periodontol 2001;6:78–86.
[14] Slots J, Zambon JJ, Rosling BG, Reynolds HS, Christersson LA, Genco RJ. Acti-
nobacillus actinomycetemcomitans in human periodontal disease. Associa-
tion, serology, leukotoxicity, and treatment. J Periodontal Res 1982;17:447–8.
[15] Damiano VV, Tsang A, Kucich U, Abrams WR, Rosenbloom J, Kimbel P, Fal-
lahnejad M, Weinbaum G. Immunolocalization of elastase in human emphy-
sematous lungs. J Clin Investig 1986;78:482–93.
[16] Yoshikawa T, Dent G, Ward J, Angco G, Nong G, Nomura N, Hirata K, Djuka-
novic R. Impaired neutrophil chemotaxis in chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 2007;175:473–9.
[17] Sapey E, Stockley JA, Greenwood H, Ahmad A, Bayley D, Lord JM, Insall RH,
Stockley RA. Behavioral and structural differences in migrating peripheral
neutrophils from patients with chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2011;183:1176–86.
[18] Ryder MI. Comparison of neutrophil functions in aggressive and chronic per-
iodontitis. Periodontol 2000 2010;53:124–37.
[19] Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y,
Brinkmann V, Zychlinsky A. Novel cell death program leads to neutrophil
extracellular traps. J Cell Biol 2007;176:231–41.
[20] Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of
innate immunity. J Immunol 2012;189:2689–95.
[21] Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS,
Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science
2004;303:1532–5.
[22] Grabcanovic-Musija F, Obermayer A, Stoiber W, Krautgartner W, Steinbacher
P, Winterberg N, Bathke AC, Klappacher M, Studnicka M. Neutrophil extra-
cellular trap (NET) formation characterises stable and exacerbated COPD and
correlates with airflow limitation. Respir Res 2015;16:59.
[23] Krautgartner WD, Klappacher M, Hannig M, Obermayer A, Hartl D, Marcos V,
Vitkov L. Fibrin mimics neutrophil extracellular traps in SEM. Ultrastruct
Pathol 2010;34:226–31.
[24] Vitkov L, Klappacher M, Hannig M, Krautgartner WD. Neutrophil fate in gin-
gival crevicular fluid. Ultrastruct Pathol 2010;34:25–30.
[25] Vitkov L, Klappacher M, Hannig M, Krautgartner WD. Extracellular neutrophil
traps in periodontitis. J Periodontal Res 2009;44:664–72.
[26] Eriksson S. Pulmonary emphysema and alpha-1 antitrypsin deficiency. Acta
Med Scand 1964;175:197–205.
[27] Fujita J, Nelson NL, Daughton DM, Dobry CA, Spurzem JR, Irino S, Rennard SI.
Evaluation of elastase and antielastase balance in patients with chronic
bronchitis and pulmonary emphysema. Am Rev Respir Dis 1990;142:57–62.
[28] Overall CM, Sodek J. Initial characterization of a neutral metalloproteinase,
active on native 3/4-collagen fragments, synthesized by ROS 17/2.8 osteo-
blastic cells, periodontal fibroblasts, and identified in gingival crevicular fluid.
J Dent Res 1987;66:1271–82.
[29] Vernooy JH, Lindeman JH, Jacobs JA, Hainemaaijer R, Wouters EF. Increased
activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in
induced sputum from patients with COPD. Chest 200 4;126:1802–10.
[30] Caton JG, Ciancio SG, Blieden TM, Bradshaw M, Crout RJ, Hefti AF, Massaro JM,
Polson AM, Thomas J, Walker C. Treatment with subantimicrobial dose dox-
ycycline improves the efficacy of scaling and root planing in patients with
adult periodontitis. J Periodontol 2000;71:521–32.
[31] Albert RK, Connett J, Bailey WC, Casaburi R, Cooper Jr JA, Criner GJ, Curtis JL,
Dransfield MT, Han MK, Lazarus SC, MakeB, Marchetti N, Martinez FJ, Madinger
NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanion PD, Sciurba
FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR, COPD Clinical
Research Network. Azithromycin for prevention of exacerbations of COPD. N
Engl J Med 2011;365:689–98.
[32] Loukides S, Bakakos P, Kostikas K. Oxidative stress in patients with COPD. Curr
Drug Targets 2011;12:469–77.
[33] Weiss SJ. Tissue destruction by neutrophils. N Engl J Med 1989;320:365–76.
[34] Kostikas K, Papatheodorou G, Psathakis K, Panagou P, Loukides S. Oxidative stress
in expired breath condensate of patients with COPD. Chest 2003;124:1373–80.
[35] Noguera A, Batle S, Miralles C, Iglesias J, Busquets X, MacNee W, Agusti AG.
Enhanced neutrophil response in chronic obstructive pulmonary disease.
Thorax 2001;56:432–7.
[36] Matthews JB, Wright HJ, Roberts A, Cooper PR, Chapple IL. Hyperactivity and
reactivity of peripheral blood neutrophils in chronic periodontitis. Clin Exp
Immunol 2007;147:255–64.
[37] Trivedi S, Lal N, Mahdi AA, Singh B, Pandey S. Association of salivary lipid
peroxidation levels, antioxidant enzymes, and chronic periodontitis. Int J
Periodontics Restorative Dent 2015;35:e14–9.
A. Ramesh et al. / Journal of Oral Biosciences 58 (2016) 23–2626