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Vancouver, BC, Canada
Drs. Sin and Man are affiliated with the James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul’s Hospital and the Department of Medicine, Division of Respirology, The University of British Columbia.
Correspondence to: Don D. Sin, MD, MPH, FCCP, James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, St. Paul’s Hospital, Room 368A, 1081 Burrard St, Vancouver, BC, V6Z 1Y6 Canada; e-mail: dsin{at}mrl.ubc.ca
Mild pulmonary hypertension is a common complication in patients with COPD, even in those without significant arterial hypoxemia, and is independently associated with poor prognosis.12 Pathologically, the pulmonary vessels in such individuals demonstrate arterial remodeling, which fails to reverse with supplemental oxygen therapy. Curiously, the remodeling process in COPD patients involves all layers of the vasculature and not just the medial (muscular) layer, as would be expected in patients with hypoxia-induced conditions,3 which suggests the involvement of other factors. Other putative causes of pulmonary hypertension in COPD patients include loss of the capillary bed secondary to emphysema, vessel compression from dynamic hyperinflation, endothelial dysfunction related to cigarette smoking, and abnormal proliferation and delayed apoptosis of smooth muscle cells secondary to genetic alterations or infectious agents.3
Although it has been known for years that inflammation plays a prominent role in the airway disease of COPD, the potential role of inflammation in the pathogenesis of vessel disease was not well-studied until the past few years. Seminal work by Peinado and colleagues4 showed that the walls of small pulmonary arteries in COPD patients are commonly infiltrated with leukocytes, especially CD8-positive lymphocytes. With disease progression, the extent of the leukocyte involvement in the vessel walls becomes more prominent, and is associated with increased wall stiffness and the failure of vessels to relax properly with adenosine diphosphate stimulation, indicating endothelial dysfunction.4
Whether systemic inflammation contributes to this process is not known. However, in other conditions that give rise to pulmonary hypertension, systemic inflammation appears to be an important cofactor in the development of pulmonary vessel disease,5 and therapies that mitigate systemic inflammation may attenuate pulmonary pressures. Even in patients with primary pulmonary hypertension, systemic inflammation may play a role, as such patients have elevated levels of tumor necrosis factor (TNF)-
and interleukin (IL)-6 in the systemic circulation compared to individuals without pulmonary hypertension.6 These clinical observations are supported by in vitro models that demonstrate the synergistic effects of inflammation and hypoxia in down-regulating nitric oxide production and inducing endothelial dysfunction in the pulmonary vasculature.7
The study by Joppa and colleagues8 in this issue of CHEST (see page 326) suggests that systemic inflammation may also play a major role in pulmonary hypertension in COPD patients. The authors carefully selected 43 consecutive patients with moderate-to-severe COPD (mean FEV1, 46% predicted), and performed a variety of clinical, physiologic, and biochemical measurements to determine the relationship between systemic inflammation and pulmonary arterial hypertension. They found that patients with significant pulmonary hypertension had higher levels of circulating C-reactive protein (CRP) and TNF-. Furthermore, there was a significant linear relationship between serum CRP levels and systolic pulmonary artery pressure in these patients, further emphasizing the likely importance of systemic inflammation in COPD-related pulmonary hypertension. Interestingly, PaO2 and serum log-CRP levels were the only two significant predictors of systolic pulmonary arterial pressure, and collectively they accounted for 37% of its variation, which is consistent with data from in vitro models,7 demonstrating the importance of hypoxia and inflammation in inducing endothelial dysfunction in pulmonary vessels.
There were many strengths to the present study, as follows: the detailed collection of lung function and blood gas measurements; the blinding of the echocardiographer to the results of the biochemical measurements; and the sophisticated modeling process to mitigate confounding. There were also some limitations. Due to the cross-sectional nature of the data collection, the direction of causation could not be determined. While we believe that systemic inflammation was at least partially responsible for pulmonary hypertension, reverse causation could not be entirely ruled out. Additionally, we cannot discount the possibility that the vasculature changes may have reflected the "spillage" of inflammation from adjacent airway tissues and was not dependent on systemic inflammation per se. It was also possible that a third (unmeasured and unaccounted) factor could have explained the relationship. For example, since systemic inflammation relates to COPD severity, other factors associated with disease progression, such as dynamic hyperinflation, pulmonary emphysema, and oxidant/antioxidant imbalances, could have contributed to the pulmonary hypertension. Although CRP is a robust marker of systemic inflammation, there is little consensus as to whether or not it is a pivotal molecule in effecting vascular disease.9 It is plausible that CRP is merely a biomarker of some other sentinel molecules that may be primarily responsible for pulmonary hypertension in COPD patients. Potential candidate molecules include IL-1ß, TNF-, IL-6, endothelins, 5-hydroxytryptamine, transforming growth factor-ß, and many others.13 Finally, while two-dimensional Doppler echocardiography is a reasonable and noninvasive method of ascertaining pulmonary arterial pressures, the results are more variable and less reliable in patients with hyperinflated lungs.10
Notwithstanding these limitations, the findings from the present study have raised the following very important new (and testable) hypothesis in COPD: that systemic inflammation may be involved in the pathogenesis of pulmonary hypertension. The challenge for the COPD research community is to determine the validity of this hypothesis through well-designed clinical and animal studies. COPD is one of the fastest growing diseases globally and is projected to be the third leading cause of mortality worldwide within 10 years.11 The presence of pulmonary hypertension dramatically worsens the already dismal prognosis of COPD patients.2 There is therefore a pressing need to develop new therapeutic compounds to combat the epidemic of COPD morbidity and mortality, and to this end the study by Joppa and colleagues has raised systemic inflammation as a potential target for novel discoveries.
Footnotes
The authors have received honoraria for speaking engagements from GlaxoSmithKline (GSK) and AstraZeneca, and for consultative services from GSK. They have also received research funding from GSK. The two companies make antiinflammatory products for the treatment of airway diseases.
References
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