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BPCO: una sindrome infiammatoria sistemica cronica?
Pierpaolo isidori
U.O. Medicina Interna e Pneumologia
Ospedale Fossombrone/Fano
Chronic obstructive pulmonary disease (COPD) is
characterised by poorly reversible airflow limitation that is
usually progressive and associated with an abnormal
inflammatory response of the lungs to noxious particles or
gases, particularly cigarette smoke
The chronic airflow obstruction is due to the presence of
specific abnormalities of both the airways (bronchitis and
bronchiolitis) and the pulmonary parenchyma (emphysema)
that were associated with an inflammatory reaction of the
airways, alveoli, and pulmonary vessels
Chronic obstructive pulmonary disease: molecular and cellular mechanisms
Barnes PJ, Shapiro SD, Pauwels RA. Eur Respir J 2003;22:672–688.
Fisiopatologia
INFIAMMAZIONE
RIDUZIONE DEL
FLUSSO AEREO
Patologia piccole vie aeree
Infiammazione bronchiale
Rimodellamento bronchiale
Distruzione parenchimale
Perdita attacchi alveolari
Riduzione tono elastico
Patologia: vie aeree centrali
• ipertrofia ghiandole bronchiali
e metaplasia globet cell con
eccessiva produzione di muco
• metaplasia squamosa dell’epitelio delle vie aeree, perdita
di cilia e disfunzione ciliare, aumentato spessore del
muscolo liscio e del tessuto connettivo
• nella parete delle vie aeree centrali sono presenti linfociti
(CD8+) ma col progredire della malattia predominano i
neutrofili; negli spazi aerei linfociti, neutrofili e macrofagi
• una bronchiolite è
presente in uno
stadio iniziale
• vi è estensione di globet cell
e metaplasia squamosa
• le cellule presenti nelle pareti e negli spazi aerei sono simili
a quelle delle vie aeree maggiori
• negli stadi avanzati vi è fibrosi e aumentata deposizione di
fibre collagene
Patologia:vie aeree periferiche
Patologia: parenchima polmonare
perdita di pareti alveolari, allargamento degli spazi alveolari
e ridotti attacchi alveolari che contribuiscono al collasso delle vie aeree
• centrolobulare: dilatazione e distruzione dei bronchioli
• panlobuilare: distruzione dell’intero acino
Patologia: vasi polmonari
• ispessimento della parete dei
vasi e alterazione dell’endotelio
• aumento di spessore del
muscolo liscio e infiltrato
Infiammatorio (macrofagi e
linfociti T CD8+)
• deposizione di collagene e
distruzione enfisematosa
del letto capillare
Inflammatory reaction in COPD
This abnormal inflammatory reaction can also be
detected in the systemic circulation.
It is likely that this systemic inflammation contributes
significantly to the pathobiology of numerous
extrapulmonary effects of the disease - the socalled
systemic effects of COPD
Given that COPD is associated with an abnormal
inflammatory response of the lung parenchyma to inhaled
pollutant and gases (mostly through cigarette smoking), the
most obvious explanation for the presence of systemic
inflammation in these patients was that, somehow, this
pulmonary inflammation was “spilling over” into the
systemic circulationAgustì A. Proc Am Thorax Soc 2007;4:552
BPCO patologia respiratoria
con implicazioni sistemiche
The most common comorbidities described in
association with COPD are skeletal muscle
abnormalities,hypertension, diabetes, coronary-
artery disease, heart failure, pulmonary infections,
cancer, and pulmonary vascular disease
Chronic comorbid diseases affect health outcomes
in COPD; in fact, patients with COPD mainly die of
non-respiratory disorders such as cardiovascular
diseases ( ca. 25%) or cancer (mainly lung cancer, 20–33%)
Agustì A. Proc Am Thorax Soc 2007;4:552
Increasing evidence suggests that clinical features of
COPD and airflow limitation are poorly correlated.
Patients with COPD have systemic manifestations that are not
reflected by the FEV1.
The BODE index, a simple multidimensional grading system,
including the body-mass index, FEV1 as a percentage of the
predicted value, score on the MMRC dyspnea scale, and the
distance walked in six minutes,is better than the FEV1 at
predicting the risk of death from any cause and from respiratory
causes among patients with COPD
The Body-Mass Index, Airflow Obstruction,Dyspnea, and Exercise Capacity Indexin COPD
BR Celli. NEJM 2004; 350:1005-12
BR Celli. NEJM 2004; 350:1005-12
COPD is associated with low-grade systemic inflammation
A recent meta-analysis confirmed that patients with
stable COPD present increased numbers of leukocytes
(some of them with an activated phenotype) and
Increased levels of acute phase response proteins (C-
reactive protein [CRP] and fibrinogen) and cytokines
(IL-6) and tumor necrosis factor (TNF)
The intensity of this systemic inflammation increases
during exacerbations of COPD
Gan WQ et al., Thorax 2004;59:574–580
Systemic Effects of COPD
Agustì A. Proc Am Thorax Soc 2007;4:552
COPD can no longer be judged a disease only of the lungs, as it is
often associated with a wide variety of systemic consequences
other chronic conditions, such as chronic heart failure, obesity,or diabetes, and even the normal process of aging, also appear to be associated with a similar low-grade systemic inflammatory process
add the term “chronic systemic inflammatory syndrome” to the diagnosis of COPD
stimulate discussion around the frequent complex chronic comorbidities in people with COPD and to provoke a new view of the disease in general
From COPD to chronic systemic inflammatory syndrome?
LM Fabbri, KF Rabe Lancet 2007; 370: 797–99
chronic refers to the slow and progressive
development of the abnormalities
systemic refers to the fact that risk factors act directly or indirectly on all target organs simultaneously
inflammatory refers to the association of all components with inflammation
syndrome refers to the association of several clinically
recognisable features, signs, symptoms, or characteristics
that generally arise together, so that the presence of one
feature alerts the doctor to the presence of the others
Chronic systemic inflammatory syndrome
LM Fabbri, KF Rabe Lancet 2007; 370: 797–99
Cigarette smoking is the major risk factor for COPD and is
one of the most important risk factors for all chronic
diseases and some cancers. It causes lung and systemic
inflammation, systemic oxidative stress, marked changes
of vasomotor and endothelial function
Systemic effects of smoking could contribute substantially
to the development not only of the airways and lung
abnormalities characteristic of COPD but also of chronic
diseases - eg, cardiovascular diseases, metabolic
disorders, and some cancers that are induced by smoking
in combination with or without other risk factors such as
obesity, hyperlipidaemia, and increased blood pressure
Comorbidities in COPD
Sevenoaks M, Stockley R. Respir Res 2006; 7: 70
The central role of inflammation in comorbidity is associated with COPD
LM Fabbri et al Eur Respir J 2008; 31: 204–212
Diagnostic components of chronic systemic inflammatory syndrome
Age older than 40 years
Smoking for more than 10 pack-years
Symptoms and abnormal lung function compatible
with COPD
Chronic heart failure
Metabolic syndrome
Increased C-reactive protein
At least three components are needed for
diagnosis
LM Fabbri, KF Rabe Lancet 2007; 370: 797–99
Diagnostic components of chronic systemic inflammatory syndrome
COPD, chronic heart failure, and metabolic syndrome are
diagnosed according to current international guidelines
after comprehensive assessment of lung, cardiac, and
metabolic functions
Other chronic disorders, such as coronary and peripheral
artery diseases, anaemia, osteoporosis, and rheumatoid
arthritis, could be included either as additional
comorbidities, as complications (eg, steroid-induced
osteoporosis), or as independent modifiers of severity of
the chronic syndrome (eg,depression)
LM Fabbri, KF Rabe Lancet 2007; 370: 797–99
SYSTEMIC INFLAMMATION INCHRONIC OBSTRUCTIVE PULMONARY DISEASE:FACTS AND UNKNOWNS
Facts Low-grade systemic inflammation occurs in patients with
clinically stable COPD (and in many other chronic diseases,
including the physiologic process of aging)
In COPD, systemic inflammation persists after quitting smoking and increases during exacerbations of the disease
Steroid therapy (both inhaled and oral) decreases systemic
inflammatory markers in patients with stable COPD
The origin of systemic inflammation in COPD is likely to be
multifactorial. The identification of the different factors
potentially contributing to it and their relative importance
needs to be established.
Agustì A. Proc Am Thorax Soc 2007;4:552
Unknowns
Why systemic (and pulmonary) inflammation persists after quitting smoking is a key question that is so far unanswered.
It is likely (but currently unproven) that systemic inflammation contributes to the pathophysiology of many systemic effects of COPD, including skeletal muscle dysfunction, cardiovascular disease, and osteoporosis.
The impact on relevant clinical outcomes, such as mortality or health status, of a pharmacologically induced reduction of systemic inflammation in COPD is unproven.
Agustì A. Proc Am Thorax Soc 2007;4:552
SYSTEMIC INFLAMMATION INCHRONIC OBSTRUCTIVE PULMONARY DISEASE:FACTS AND UNKNOWNS
Pharmacological treatment
Cardiovascular drugs have already been reported to have
beneficial effects in COPD. Statins, which are used
mainly as lipid-lowering agents for treatment of metabolic
syndrome, have potent anti-inflammatory properties that
positively affect COPD, chronic heart failure, and vascular
diseases (1)
Similarly, drugs developed and used to treat
respiratory diseases (eg, inhaled bronchodilators and
steroids) could have substantial beneficial effects for
cardiovascular diseases (2)
1) Calverley PM et al. N Engl J Med 2007; 356: 775–89
2) Sin DD, Man SF. Curr Opin Pulm Med 2007;13: 90–97
Effect of simvastatin
on cigarette smoke-induced
emphysema in rats
Control Smoke
Smoke+statin Statin
Lee JH et al: AJRCCM 2005
↓ Inflammatory cells
↓ MMP-9
↓ eNOS
↓ Pulmonary vascular
remodelling
STATIN IN COPD
Journal of the American College of Cardiology
2006;47:2554-60.
Sin and coworkers showed that, first, the withdrawal of inhaled corticosteroids in patients with COPD increased the plasma levels of CRP, a well-established marker of systemic inflammation,by about 30%. Second, they showed that 2 weeks of treatment with inhaled fluticasone (or oral prednisolone) reduced them by about 50%
A retrospective study has suggested that the risk of acute myocardial infarction in patients with COPD was reduced by 32% in those receiving low doses of inhaled steroids
Pharmacological treatment
Sin DD et al, Am J Respir Crit Care Med 2004;170:760–765
Huiart L et al, Eur Respir J 2005;25:634–639
CONCLUSIONI
COPD is a multicomponent disease characterized by pulmonary
and systemic inflammation.
The origin of the latter is unclear and probably multifactorial.
It is likely to be a major contributor to the pathobiology of many
(if not all) of the extrapulmonary effects of COPD, including
skeletal muscle atrophy and dysfunction and cardiovascular
disease.
Available evidence suggests that systemic inflammation in COPD
can be reduced by steroid therapy (both oral and inhaled). The
potential effects of this observation on clinically relevant
outcomes in these patients (e.g., mortality, health status) remain
to be demonstrated, but open a new avenue to improve the
therapy and care of patients with this devastating disease.
Cigarette smoke
(and other irritants)
PROTEASESNeutrophil elastase
Cathepsins
Matrix metalloproteinases
Alveolar wall destruction(Emphysema)
Mucus hypersecretion(Chronic bronchitis)
Fibrosis
(Sm airways)
Fibroblast
TGF-β
CTG
Neutrophil
Chemotactic factors
CD8+
lymphocyte
Monocyte
Alveolar macrophageEpithelial
cells
INFLAMMATORY MECHANISMS IN COPD
Domande ancora senza una
risposta………
• Potrebbe il trattamento anti-infiammatorio polmonare ridurre il
rischio di eventi cardiaci acuti?
• Potrebbe il trattamento anti-infiammatorio polmonare ridurre il
rischio di progressione dell’aterosclerosi?
• Potrebbe il trattamento anti-infiammatorio polmonare ridurre il
rischio di eventi trombotici?
• Il trattamento della malattia cardiaca può influenzare la
progressione della malattia polmonare?
Lo pneumologo nell’ambito di questo scenario ha senza dubbio
competenze, sensibilità e cultura per contribuire in modo concreto e
pratico alla ricerca in questo campo
Systemic effects of Chronic obstructive
pulmonary disease Weight loss, nutritional abnormalities, and
skeletal muscle dysfunction are well-recognized systemic effects of COPD. Otherless well known but potentially important systemic effects include an increased risk of cardiovascular disease and several neurologic and skeletal defects.
The mechanisms underlying these systemic effects are unclear, but they are probably interrelated and multifactorial, including inactivity, systemic inflammation, tissue hypoxia and oxidative stress among others.
Agustì A. Proc Am Thorax Soc 2007;4:552
Chronic medical conditions COPD is associated with chronic heart failure in more than
20% of
patients and with osteoporosis in up to 70% of patients, in
part,
independently from treatment with steroids, decreased
physical activity, or both. (Rutten FH et al. Eur J Heart Fail 2006; 8: 706–
11.)
In a small study, almost 50% of patients with COPD had
one or more components of the metabolic syndrome (Marquis
K et al. J Cardiopulm Rehabil 2005; 25: 226–32).
Conversely, chronic heart failure is associated, in more
than 50% of patients, with arterial hypertension and
coronary or peripheral artery diseases, with diabetes
in 20–30%, and with anaemia in 20–30%. (Dahlstrom U.. Eur J
Heart Fail 2005; 7: 309–16.)
Type 2 diabetes is linked to hypertension in more than
70% of individuals and to cardiovascular diseases and
obesity in more than 80% (Walker CG et al. Clin Sci (Lond) 2007; 112: 93–111.)
Diabetes is independently associated with reduced lung
function, which together with obesity could further worsen
the severity of COPD (Poulain M et al. CMAJ 2006; 174: 1293–99).
Chronic medical conditions
COPD and cardiovascular disease
Agustì A. Proc Am Thorax Soc 2007;4:552
The major risk factor for the development of COPD is cigarette smoking. Smoking is also a major risk factor for a large number of other illnesses, including cardiovascular disease. As a result of sharing common risk factors, patients with COPD are at further increased risk to suffer these comorbidities.
Among patients with COPD, comorbidities are extremely common for a number of reasons.
COPD is a disease that increases in importance with age. Because most chronic disorders of adults also increase with age, statistically, comorbidities will be relatively common among patients with severe COPD.
Almost half of all people aged 65 years or
older have at
least three chronic medical conditions, and a
fifth have
five or more
Boyd CM et al.JAMA 2005; 294: 716–24
Chronic medical conditions
Pharmacological treatment Since pharmacological treatment of chronic
diseases—particularly COPD—is mainly symptomatic, a more comprehensive approach to management of COPD and its comorbidities might provide an opportunity to modify the natural history ofCOPD, allowing for identification of novel targets for treatment.
This idea is especially relevant for disorders that seem to be more preventable and treatable than COPD, such as cardiovascular and metabolic disorders.
van der Harst P et al. Cardiovasc Res 2006; 3: e333.
Mancini GB, et al. J Am Coll Cardiol 2006; 47: 2554–60.
Sfortunatamente esiste una mancanza di specifiche
raccomandazioni per il management dei pazienti con
BPCO e concomitante malattia cardiaca.
Le più recenti linee guida (Global Initiative for Chronic
Obstructive Lung Disease(GOLD) ed dell’ American
Thoracic Society/European Respiratory Society)
sebbene riconoscano che la malattia cardiaca è
spesso presente come comorbilità della BPCO, non
forniscono specifiche e dettagliate raccomandazioni di
come nella pratica clinica questi pazienti devono
essere valutati e trattati.
Pharmacological treatment
La BPCO non è descritta nelle linee guida dell’OBESITA’ e dell’IPERTENSIONE e non è inclusa nella lista dei fattori di rischio cardiaco delle linee guida delle malattie cardiovascolari.
In assoluto esiste una mancanza di raccomandazioni che guidano il clinico nella cura specifica dei pazienti con BPCO che sono affetti da obesità, ipercolesterolemia, ipertensione arteriosa, o altri fattori di rischio.
Pharmacological treatment
Main COPD comorbidities recently reported
G. Viegi et al, Eur Respir J 2007; 30: 993–1013
LiverIL-6, TNF-α, IL-1βIL-6
CRP
Cardiovascular disease Muscle wasting
Skeletal muscle
Other
Inflammatory
diseases
Circulation
SYSTEMIC EFFECTS OF COPD
Systemic effects
of smoking
Side effects ++
Potentially, the common mechanism by which major risk factors such as smoking, hyperlipidaemia, obesity, and hypertension lead to chronic disease is systemic inflammation.
C-reactive protein is almost invariably
increased in all components of the chronic systemic inflammatory syndrome, suggesting that this acute-phase protein could represent the sentinel biomarker to all chronic diseases.
Comorbidities in COPD
MacNee W.. Proc Am Thorac Soc 2005;2: 50–60.
Comorbidities are common among patients with COPD for several reasons. One is purely statistical: middle-aged and elderly patients are most often afflicted with COPD, and comorbidities become more common as age increases. Also, although smoking is linked to COPD, it is also a major risk factor for numerous other illnesses, including cardiovascular disease. However, epidemiologists evaluating the risk of heart disease have consistently shown an increased risk among patients with COPD, even when the data are ―corrected‖ for smoking. Additionally, oxidative stress and systemic inflammation are mechanically linked to the extrapulmonary manifestations in COPD
Comorbidities in COPD
(Man, 2005)