Intimal enlargement of pulmonary arteries is an early change in chronic obstructive pulmonary disease (COPD). The cellular and extracellular components that are involved in this enlargement are unknown. The present study was designed to characterize the structural changes occurring in pulmonary muscular arteries in the initial disease stages.Lung specimens from patients with moderate COPD (n=8; forced expiratory volume in one second (FEV₁), 66±10% predicted) and smokers without airflow obstruction (n=7; FEV₁, 86±6% pred), were investigated by histochemistry to characterize extracellular matrix proteins and by immunohistochemistry to identify intrinsic cells of the vascular wall.In both COPD patients and smokers, the majority of cells present in the enlarged intimas were stained by specific smooth muscle cell (SMC) markers. No staining with endothelial or fibroblast markers was shown. A proportion of SMCs did not stain with desmin, suggesting cellular heterogeneity in this population. Elastin was the most abundant extracellular matrix protein and collagen was seen in a lower proportion. The amount of collagen was related to the intimal thickness (p<0.001).The findings demonstrated smooth muscle cell proliferation, as well as elastin and collagen deposition, in the thickened intimas of pulmonary arteries in moderate chronic obstructive pulmonary disease patients and smokers, suggesting that these abnormalities may originate at an early stage in cigarette smoke-induced respiratory disease.

Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). Its presence is associated with shorter survival and worse clinical evolution. In COPD, pulmonary hypertension tends to be of moderate severity and progresses slowly. However, transitory increases of pulmonary artery pressure may occur during exacerbations, exercise and sleep. Right ventricular function is only mildly impaired with preservation of the cardiac output.Structural and functional changes of pulmonary circulation are apparent at the initial stages of COPD. Recent investigations have shown endothelial dysfunction and changes in the expression of endothelium-derived mediators that regulate vascular tone and cell growth in the pulmonary arteries of patients with mild disease. Some of these changes are also present in smokers with normal lung function. Accordingly, it has been postulated that the initial event in the natural history of pulmonary hypertension in COPD could be the lesion of pulmonary endothelium by cigarette-smoke products.Long-term oxygen administration is the only treatment that slows down the progression of pulmonary hypertension in chronic obstructive pulmonary disease. Nevertheless, with this treatment pulmonary artery pressure rarely returns to normal values and the structural abnormalities of pulmonary vessels remain unaltered. Vasodilators are not recommended on the basis of their minimal clinical efficacy and because they impair pulmonary gas exchange. Recognition of the role of endothelial dysfunction in the physiopathology of pulmonary hypertension in chronic obstructive pulmonary disease opens new perspectives for the treatment of this complication.

Rationale: Inflammation and oxidative stress contribute to muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD). Oxidants contained in cigarette smoke (CS) induce adverse effects on tissues through oxidative phenomena. Objectives: To explore oxidative stress and inflammation in quadriceps of human smokers and in diaphragm and limb muscles of guinea pigs chronically exposed to CS. Methods: Muscle function, protein oxidation and nitration, antioxidants, oxidized proteins, inflammation, creatine kinase activity, and lung and muscle structures were investigated in vastus lateralis of smokers, patients with COPD, and healthy control subjects and in diaphragm and gastrocnemius of CS-exposed guinea pigs at 3, 4, and 6 months. Measurements and Main Results: Compared with control subjects, quadriceps muscle force was mildly but significantly reduced in smokers; protein oxidation levels were increased in quadriceps of smokers and patients with COPD, and in respiratory and limb muscles of CS-exposed animals; glycolytic enzymes, creatine kinase, carbonic anydrase-3, and contractile proteins were significantly more carbonylated in quadriceps of smokers and patients with COPD, and in respiratory and limb muscles of CS-exposed guinea pigs. Chronic CS exposure induced no significant rise in muscle inflammation in either smokers or rodents. Muscle creatine kinase activity was reduced only in patients with COPD and in both diaphragm and gastrocnemius of CS-exposed animals. Guinea pigs developed bronchiolar abnormalities at 4 months of exposure and thereafter. Conclusions: CS exerts direct oxidative modifications on muscle proteins, without inducing any significant rise in muscle inflammation. The oxidative damage to muscle proteins, which precedes the characteristic respiratory changes, may contribute to muscle loss and dysfunction in smokers and patients with COPD.

Endothelial dysfunction and intimal thickening have been shown in pulmonary arteries (PA) of patients with mild chronic obstructive pulmonary disease (COPD). To investigate whether an inflammatory process related to tobacco smoking might be involved in the development of pulmonary vascular abnormalities in COPD, we characterized the inflammatory cell infiltrate and the endothelium-dependent relaxation in PA of 39 patients who underwent lung resection, divided into three groups: “nonsmokers” (n = 7); “smokers,” with normal lung function (n = 12); and “COPD” (n = 20). Endothelium-dependent relaxation was assessed in vitro by exposing PA rings to adenosine diphosphate (ADP). Inflammatory cell types were identified by immunohistochemistry. PA of COPD patients developed lower relaxation in response to ADP than nonsmokers and smokers. The number of inflammatory cells was increased in PA of COPD compared with the other two groups. This cell infiltrate was largely constituted by T lymphocytes. The CD8⁺ T-cell subset was increased in both smokers and COPD compared with nonsmokers, yielding a reduction of the CD4⁺/CD8⁺ ratio. The intensity of the inflammatory infiltrate correlated with both the endothelium-dependent relaxation and the intimal thickness. We conclude that cigarette smoking induces a CD8⁺ T-lymphocyte infiltrate in PA, which is associated with the impairment of the vessel's structure and function, suggesting the potential involvement of an inflammatory process in the pathogenesis of pulmonary vascular abnormalities in the early stage of COPD.

To investigate whether endothelial dysfunction of pulmonary arteries (PA) is present in patients with mild chronic obstructive pulmonary disease (COPD) and to what extent it is related to the morphological abnormalities of PA, we studied 41 patients who underwent lung resection. Patients were divided into the following groups: nonsmokers (n = 7), smokers with normal lung function (n = 13), and COPD (n = 21). Endothelium-dependent relaxation mediated by nitric oxide was evaluated in vitro in PA rings exposed to cumulative concentrations of acetylcholine (ACh) and ADP. Structural abnormalities of PA were assessed morphometrically. PA of COPD patients developed lower maximal relaxation in response to ADP than both nonsmokers and smokers (P < 0.05 each) and a trend to reduced relaxation in response to ACh (P = 0.08). Maximal relaxation to ADP correlated with the degree of airflow obstruction (r = 0.48,P < 0.01). Morphometrical analysis of PA revealed thicker intimas, especially in small arteries, in both smokers and COPD compared with nonsmokers (P < 0.05 each). We conclude that endothelial dysfunction of PA is already present in patients with mild COPD. In these patients, as well as in smokers with normal lung function, small arteries show thickened intimas, suggesting that tobacco consumption may play a critical role in the pathogenesis of pulmonary vascular abnormalities in COPD.