Rethinking chronic obstructive pulmonary disease

Rethinking chronic obstructive pulmonary disease

Medical Hypotheses 76 (2011) 358–360 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: Re...

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Medical Hypotheses 76 (2011) 358–360

Contents lists available at ScienceDirect

Medical Hypotheses journal homepage:

Rethinking chronic obstructive pulmonary disease Antonella Tonello a,⇑, Giovanni Poli b a b

Laboratorio di Analisi, Ospedale Mater Salutis, Legnago, Verona, Italy Istituto di Chimica e Microscopia Clinica, Dipartimento di Scienze Morfologico-Biomediche, Ospedale Policlinico G.B. Rossi, Verona, Italy

a r t i c l e

i n f o

Article history: Received 2 September 2010 Accepted 24 October 2010

a b s t r a c t Chronic obstructive pulmonary disease (COPD) is a complex polygenic disease characterized by an abnormal inflammatory response to smoke, and results in a progressive and debilitating condition with declining lung function. The reasons why some smokers get COPD are not known. We suggest that corticosteroid resistance, which derives from oxidative stress, might actually be the cause of COPD and represent the starting point of the pathology. The absence of response to corticosteroids would let the disease develop, impairing the organism capacity to suppress any kind of inflammatory process. Corticosteroid resistance may derive from smoke induced oxidative stress and plausibly impairs the organism capacity to suppress inflammation. Many factors may contribute to the development and persistence of corticosteroid resistance: inefficient antioxidant defences, a corticosteroid response less efficient or more sensitive to oxidative conditions, and also any other concomitant factor, environmental, genetic or intercurrent, which would contribute to amplify inflammation and hence oxidative stress. One or more of these factors might represent the variable component of the disease, which gives origin to COPD heterogeneity. This hypotheses may also explain why the disease persists after quitting smoking, as an inflammatory process severe enough to generate a strong oxidative stress may support itself by maintenance of corticosteroid resistance. Ó 2010 Elsevier Ltd. All rights reserved.

Introduction Chronic obstructive pulmonary disease (COPD) is a major global health problem that, in 2002, was the fifth leading cause of death in the world. According to new estimates for 2020, COPD is predicted to become the third leading cause of death [1]. The pathogenesis of COPD is based on the body’s response to inhaled toxic particles and gases. Although tobacco smoking is the major source of this type of insult, other types of factors such as biomass fuel smoke contribute to the risk of developing COPD [2]. COPD is defined as a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response. The inflammatory response affects both airways and parenchyma and is characterized by thickening, fibrosis, and narrowing of the small conducting airways, and emphysematous destruction of the lungs’ elastic properties [3]. Smoke is a major source of particles, free radicals and reactive chemicals, all of which can produce an overwhelming oxidant burden on the lungs [4]. The molecular effect of these highly reactive molecules can explain a number of pathologies observed in COPD ⇑ Corresponding author. Tel.: +39 (0)442 622634; fax: +39 (0)442 622705. E-mail addresses: [email protected] (A. Tonello), [email protected] (G. Poli). 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.10.039

patients [4]; however, only a minority of smokers is diagnosed with clinically relevant COPD, suggesting that COPD is the result of host–environmental interaction, most probably genetically predetermined [5]. The cellular and molecular mechanisms that facilitate the progression toward the disease or its evasion are not known. COPD is characterized by corticosteroid resistance, as even high doses of corticosteroids have a minimal effect on the inexorable decline in lung function in COPD patients and have only a small effect in reducing COPD exacerbations [6]. Corticosteroid resistance is considered a major problem for therapy, but its implications in COPD pathogenesis are not clear. Corticosteroid resistance entails not only unresponsiveness to anti-inflammatory drugs, but also unresponsiveness to endogenous cortisol. Corticosteroids and the hypothalamus pituitary adrenal (HPA) axis are crucial for maintaining physiological homeostasis; they regulate intermediary metabolism and numerous tissue-specific activities including immune function, the inflammatory response, embryogenesis, behaviour, and cell proliferation and survival [7]. Corticosteroids have well known anti-inflammatory actions and may also enhance innate immunity [8,9]. Corticosteroid resistance seems to be intrinsic to smoke exposition, as active smoking impairs the efficacy of short-term oral corticosteroid treatment in chronic asthma [10]. Given these premises, we propose that corticosteroid resistance induced by oxidative stress might be the initiatory component of

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COPD, which would impair the organism capacity to suppress inflammation, whatever its origin. Persistent corticosteroid resistance may expose to the deleterious effects of excessive and chronic inflammation and might be the constant factor that differentiates COPD patients from healthy smokers. The analysis of the origin of corticosteroid resistance in case of oxidative stress may support this hypotheses.

Corticosteroid resistance and oxidative stress Corticosteroids are the most effective anti-inflammatory treatments available for many inflammatory and immune diseases, but COPD, interstitial pulmonary fibrosis, acute respiratory distress syndrome, and cystic fibrosis, seem to be largely corticosteroid resistant [6]. Numerous mechanisms can contribute to this resistance, but in COPD, severe asthma and smoking asthma the main cause of corticosteroid resistance seems to be oxidative stress [6,11,12]. Oxidative stress can impair corticosteroid signalling at pre-receptor [12], receptor [11,13–15] and post-receptor levels [6,11]. Pre-receptor corticosteroid resistance Levels of circulating cortisol are controlled systemically by the HPA axis and locally by the action of 11b-hydroxysteroid dehydrogenase (11b-HSD) enzymes, which interconvert cortisol and its inactive metabolite, cortisone [7]. This dual regulation ensures the maintenance of corticosteroid homeostasis and perturbations of either of these systems contribute to the development of diseases of metabolic origin. Two 11b-HSD isoforms have been characterized and are expressed in lung tissue and immunity cells. 11b-HSD2 is an oxidase which inactivates cortisol, whereas 11bHSD1 acts as a reversible ketoreductase by virtue of the intracellular localization within the lumen of the endoplasmic reticulum in proximity to the hexose-phosphate dehydrogenase (H6PD) [16]. H6PD couples the oxidation of glucose-6-phosphate to the reduction of nicotinamide adenine dinucleotide phosphate (NADPH). It is the generation of NADPH within the endoplasmic reticulum adjacent to 11b-HSD1 that drives its reaction direction. In the human lung in case of cigarette smoke exposition, cellular oxidative stress also involves the endoplasmic reticulum, where the ‘‘unfolded protein response’’ is induced [17]. Oxidative stress may impair the regeneration of endoplasmic NADPH and so 11b-HSD1 may not be able to work as reductase, but only as oxidase [12]. Receptor corticosteroid resistance Corticosteroids signal through genomic and non-genomic pathways. The classic, genomic actions of corticosteroids are mediated through cytosolic corticosteroid receptor, which is a member of the nuclear receptor superfamily of ligand-dependent transcription factors. After ligand binding, the receptor undergoes an initial conformational change that results in the exposure of its nuclear localization signal, followed by nuclear entry. Studies in vitro show that the corticosteroid receptor stability and nuclear import are impaired in oxidative conditions, whereas a reduction state strengthen the corticosteroid response through receptor protein stabilization [11,13]. In vivo the corticosteroid receptor level in the peripheral blood leukocytes of COPD patients decreases with increasing oxidative stress [14] and expression in the lungs of patients with COPD is reduced compared with smokers with normal lung function [15]. This reduction may take corticosteroid receptor levels below the threshold needed for effective corticosteroidmediated inflammatory repression [15].


Post-receptor corticosteroid resistance Ligand-activated corticosteroid receptor influences gene transcription in various ways, by both induction and repression. The anti-inflammatory properties of corticosteroids involve repression: within the nucleus, corticosteroid receptor is able to recruit corepressor proteins such as histone deacetylase (HDAC) 2 to actively transcribing gene complexes, which in turn results in the suppression of proinflammatory genes [6,11]. Oxidative stress causes HDAC2 expression and activity to be reduced in BAL fluid macrophages, bronchial biopsy specimens, and peripheral lung tissue from patients with COPD, and in the peripheral blood cells of asthmatic patients who smoke compared to non-smokers [6,11]. The presented mechanisms of corticosteroid resistance highlight that corticosteroid signals depend on the cellular redox state. Corticosteroid signals are impaired by an excessively oxidized state, whatever the origin and the specific bioactivity of the triggering factor. The variable components of COPD Healthy smokers activate efficient antioxidant defences which confer protection to smoke induced oxidative stress. COPD patients fail in the protection against oxidative stress and consequently develop corticosteroid resistance, which may determine the incapacity to suppress inflammation of any origin and, in our hypotheses, would be the starting point of the disease. Inefficient antioxidant defences or a corticosteroid response less efficient or more sensitive to oxidative conditions are genetic factors that may contribute to the development of corticosteroid resistance. Interestingly, Schoorlemmer et al. found that men with high serum total or high serum free cortisol had a significantly lower risk of chronic nonspecific lung diseases, including asthma and COPD [18]. Other genetic predispositions, environmental factors and also intercurrent diseases might contribute both to corticosteroid resistance development and to progress of COPD, in so far as they induce oxidative stress, even if only via inflammation. Alpha1-antitrypsin deficiency, asthma, air pollution, occupational exposure to dusts and gases and infections are clearly associated with COPD pathology. The incapacity to suppress inflammation of any origin may explain why COPD is an extremely heterogeneous disorder. The proposed hypotheses may also furnish an explanation to the fact that the inflammatory response elicited by, mostly, tobacco smoking in susceptible individuals does not resolve and persists after quitting. In fact, an inflammatory process severe enough to generate a strong oxidative stress may support itself by maintenance of corticosteroid resistance. Corticosteroid resistance may also increase susceptibility to airway infections, as glucocorticoids promote innate immunity in airway epithelium [8,9]. The airway epithelium is a central player in mucosal immunity, providing innate mechanisms of first-line host defence: it produces antimicrobial host defence molecules, proinflammatory cytokines and chemokines in response to activation via pathogen recognition receptors. In COPD patients several disruptions of innate lung defences occur [19] and respiratory pathogens, including bacteria, atypical bacteria, viruses and fungi, are often present in the airways [20]. Epithelial cell corticosteroid resistance probably contributes to weaken innate immunity and might be a principal culprit of airway microbial colonization in COPD. Conclusions COPD is recognized to be the result of abnormal control of the inflammatory response to inhaled particles and gases. It is well


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known that COPD is relatively corticosteroid resistant. We propose that oxidative stress induced corticosteroid resistance might be the cause of COPD pathology, as it impairs the organism capacity to suppress inflammation of any origin. Corticosteroid resistance may also impair innate lung immunity and predispose to chronic infections. This hypotheses might explain why COPD is so heterogeneous and also why it may persist after smoking cessation. The study of the combined effects of RU-486 and smoke exposure in animal models might test the hypotheses strength. More investigations are also needed to clarify the redox regulation of corticosteroid signalling. If confirmed this hypotheses may help to develop new therapeutic strategies to halt disease progression and perhaps new cost-effective prevention approaches.

Financial/non-financial disclosures No financial arrangements have been made; the authors have not received significant payments of other sorts.

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