The link between chronic periodontitis and COPD: a common role for the neutrophil?

Abstract

Background: The possible relationship between chronic inflammatory diseases and their co-morbidities has become an increasing focus of research. Both chronic periodontitis and chronic obstructive pulmonary disease are neutrophilic, inflammatory conditions characterized by the loss of local connective tissue. Evidence suggests an association and perhaps a causal link between the two diseases. However, the nature of any relationship between them is unclear, but if pathophysiologically established may have wide-reaching implications for targeted treatments to improve outcomes and prognosis.

Discussion: There have been a number of epidemiological studies undertaken demonstrating an independent association between chronic periodontitis and chronic obstructive pulmonary disease. However, many of them have significant limitations, and drawing firm conclusions regarding causality may be premature. Although the pathology of both these diseases is complex and involves many cell types, such as CD8 positive cells and macrophages, both conditions are predominantly characterized by neutrophilic inflammation. Increasingly, there is evidence that the two conditions are underpinned by similar pathophysiological processes, especially centered on the functions of the neutrophil. These include a disturbance in protease/anti-protease and redox state balance. The association demonstrated by epidemiological studies, as well as emerging similarities in pathogenesis at the level of the neutrophil, suggest a basis for testing the effects of treatment for one condition upon the severity of the other.

Summary: Although the evidence of an independent association between chronic periodontitis and chronic obstructive pulmonary disease grows stronger, there remains a lack of definitive studies designed to establish causality and treatment effects. There is a need for future research to be focused on answering these questions.

Figure 1

Convergence of the principal triggers of inflammation for periodontitis and common obstructive pulmonary disease on a common pathophysiological process involving neutrophil activation. In the dento-gingival cavity, plaque accumulation leads to the growth of bacteria such as Porphyromonas gingivalis and Fusobacterium nucleatum (1). The release of bacterial proteins and induction of cytokine expression (2) lead to the recruitment of activated neutrophils (3). Particulate matter from cigarette smoke (4) causes the local production of inflammatory cytokines, also leading to the local accumulation of activated neutrophils (5) and providing an oxidant stress to the local tissues (6). The products from inflammatory cells including chemoattractants, proteases and reactive oxygen species can amplify the inflammatory process whilst causing the connective tissue damage seen at both sites (7). The susceptibility to either pathology depends on a heightened downstream process, which may have a common abnormality that makes it more likely for both diseases to develop. COPD, common obstructive pulmonary disease.

Figure 2

The role of proteases and anti-proteases in tissue damage. A complex balance exists between proteases and anti-proteases that determines the presence and extent of connective tissue damage. The interplay is made more complex by interactions between various molecules. As well as being inactivated by AAT, neutrophil elastase is also inhibited by SERPINA3 and SLPI. However, neutrophil elastase has the ability to inhibit TIMP1-4 (inhibitors of MMPs) and MMPs can inactivate AAT. This complex interaction of activation/inactivation means that interpreting the balance of proteases and anti-proteases is far from straight forward. AAT, α₁-antitrypsin; MMPs, matrix metalloproteinases; SERPINA3, serine protease inhibitor gene; SLPI, secretory leucocyte protease inhibitor; TIMP, tissue inhibitors of metalloproteinase.

Figure 3

The formation of reactive oxygen species within inflammatory cells. Activation of the membrane bound NADPH-oxidase causes the reduction of the oxygen molecule to the superoxide anion, which dismutates, either spontaneously or via superoxide dismutase, to form hydrogen peroxide (1). Reactions with halide elements such as chlorine generate potent oxidants, for example hypochlorous acid (2). Alternatively, conversion to hydroxyl anion/radical can occur, catalyzed by iron in the Fenton reaction (3). Superoxide can also combine with nitric oxide to create the potent oxidant peroxynitrite (4). H₂O₂, hydrogen peroxide; HOCl, hypochlorous acid; MPO, myeloperoxidase; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; NO, nitric oxide; O2, oxygen; O2^-, superoxide; OH^-, hydroxyl anion; OH·, hydroxyl radical; ONOO^-, peroxynitrite; SOD, superoxide dismutase.

Figure 4

Schematic of neutrophil extracellular trap release. Activation of NADPH-oxidase causes reactive oxygen species generation (1). Granule components neutrophil elastase and myeloperoxidase are released. The enzyme peptidyl arginine deiminase, type IV is activated and acts to hypercitrullinate the nuclear chromatin (2). The nucleus disintegrates and DNA/histones are extruded through the cell membrane resulting in NETosis (3). NET components are able to trap microorganisms and expose them to increased local concentrations of destructive enzymes. NET, neutrophil extracellular traps.