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Published ahead of print on March 23, 2004, doi:10.1165/rcmb.2003-0394OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 216-219, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2003-0394OC

Complement Factors C3a, C4a, and C5a in Chronic Obstructive Pulmonary Disease and Asthma

Mateja M. Marc, Peter Korosec, Mitja Kosnik, Izidor Kern, Matjaz Flezar, Stanislav Suskovic and Jurij Sorli

University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia

Address correspondence to: Address correspondence to: Mateja M. Marc, M.D., University Clinic of Respiratory and Allergic Diseases, Golnik 36, 4204 Golnik, Slovenia. E-mail: mateja.marc{at}klinika-golnik.si


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Studies of animal models have shown that the activation of the complement system could have a role in chronic obstructive pulmonary disease (COPD) and asthma by promoting inflammation and enhancing airway hyperresponsiveness. We sought to determine whether the levels of complement factors C3a, C4a, and C5a are elevated at the site of inflammation in patients with COPD and patients with asthma. We analyzed the induced sputum of seven patients with COPD, ten patients with asthma, and twelve healthy nonsmokers. The concentrations of anaphylatoxins in the induced sputum were measured by cytometric bead array. We found significantly increased C5a/C5a desArg concentrations in supernatants of the induced sputum of patients with COPD (P = 0.007) and those with asthma (P = 0.002) compared with the control group. In patients with COPD the C5a/C5a desArg concentrations were significantly negatively correlated with lung diffusion coefficient (r = –0.71, P = 0.035). There was no significant difference in C3a/C3a desArg or C4a/C4a desArg measurements between the three groups of subjects. These in vivo results propose the involvement of complement factor C5a in the pathogenesis of COPD and asthma.

Abbreviations: bronchoalveolar lavage fluid, BALF • complement, C • chronic obstructive pulmonary disease, COPD • diffusion capacity of the lungs for carbon monoxide, DLCO • forced expiratory volume in 1 s, FEV1 • forced vital capacity, FVC • total number of nonsquamous cells, TNNC


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Both chronic obstructive pulmonary disease (COPD) and asthma are associated with an abnormal inflammatory response of the lungs. Previous studies suggest that the complement system may also participate in both disorders (1–5). Many of the functions of the complement pathway are mediated by the biologically active fragments C3a, C4a, and C5a, which are generated by proteolysis of C3, C4, and C5 components. C4a is released from C4 in the classical pathway of complement activation. C3a and C5a are generated not only via classical or alternative pathways of complement activation, but can also be activated directly by neutral tryptase released from mast cells and pulmonary macrophages (6, 7). It has been shown that C3 and C5 components can be synthesized locally in the lungs by alveolar type II cells (8). Studies of different animal models have shown that C3a and C5a can promote many pathogenetic features of COPD and asthma. Apart from their chemotactic role (9–12), they trigger smooth muscle contraction, enhance airway hyperresponsiveness and vascular permeability, and regulate vasodilatation in the lungs (3, 13, 14). C3a and C5a stimulate the release of histamine from basophiles and mast cells, and regulate the synthesis of eosinophilic cation protein and adhesion to endothelial cells by eosinophils (15–17). Few in vivo studies have shown C3a and C5a upregulation in bronchoalveolar lavage fluid (BALF) after segmental allergen provocation in patients with asthma (13, 18). In vivo studies in patients with COPD have only established data for anaphylatoxin levels in systemic circulation (1, 2). Therefore, the aim of our study was to evaluate the levels of anaphylatoxins C3a, C4a, and C5a at the site of inflammation in COPD and stable asthma. For this purpose, the standardized protocol for sputum induction in subjects with COPD, subjects with asthma, and healthy subjects was used.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Subjects
Seven patients with COPD (one female and six male) with a history of at least 30 pack-years of smoking (mean 37.6 ± 6.2 pack-years), a mean age of 72.3 ± 4.1 yr, had symptoms of chronic bronchitis, stable airflow limitation with a mean forced expiratory volume in first second (FEV1) of 41.1 ± 5.5%, a mean decrease of FEV1/forced vital capacity (FVC) by 24 ± 3.3% below the predicted values, and reversibility of < 11% predicted FEV1 or < 200 ml after inhaled ß-agonist administration. Mean diffusion capacity of lungs (DLCO) was 59.3 ± 4.8% of predicted values. The patients were nonatopic, free of glucocorticoid therapy in the month preceding the study. The ten patients with asthma were all female nonsmokers, with a mean age of 37.4 ± 3.6 yr, a mean FEV1 of 85 ± 6.4% of predicted values, with reversibility of obstruction, and positive provocation tests (PD20 FEV1 < 1.76 mg of metacholine). They were only receiving salbutamol. We included 12 healthy nonatopic nonsmokers in the control group, seven female and five male, with a mean age of 45 ± 3.8 yr, with normal pulmonary function tests. All subjects were free of symptoms and signs of acute upper respiratory tract infection in the month preceding the study. They were free of all other systemic diseases or malignancies. All subjects were volunteers and gave their written consent after being fully informed about the purpose and nature of the study. The study was approved by the local ethics committee for human studies.

Sputum Induction and Processing
Sputum was induced following a procedure as reported elsewhere (19). Subjects inhaled 4.5% hypertonic saline, nebulized via an ultrasonic nebulizer (PARI MASTER Type 84.0100; PARI GmbH, Starnberg, Germany) during three 5-min periods. To minimize the saliva contamination, we asked the subjects to mouthwash thoroughly and expectorate saliva into a separated container before producing sputum. At least 2 ml sputum was collected into a sterile container. The collected sputum was pooled and kept at 4°C for not more than 2 h before further processing. The volume of the whole sputum sample was determined, and an equal volume of 0.1% dithiothreitol (Sputolysin R; Calbiochem, San Diego, CA) was added. The samples were then mixed gently by a vortex mixer and incubated for 30 min at room temperature to ensure complete homogenization. After filtration and centrifugation, cell-free supernatants were frozen at –80°C until subsequent analysis. The quality of the induced sputum was assessed according to the recommendations of Pizzichini and coworkers (20). Only samples with score 7 or higher were used for further analysis. The total number of nonsquamous cells (TNNC) per ml of sputum sample was assessed using a hemocytometer. Cytospins were stained according to the May-Grünwald-Giemsa and Papnicolaou method. Differential cell counts were performed by one observer blinded to the clinical characteristics, counting 200 nonepithelial cells.

Detection of Anaphylatoxins
C3a/C3a desArg, C4a/C4a desArg, and C5a/C5a desArg concentrations were measured by Cytometric Bead Array (BD Biosciences PharMingen, San Diego, CA), which contains microparticles that are dyed to three different fluorescence intensities. Each particle is coupled with an antibody against one of three anaphylatoxines C3a, C4a, and C5a and their desArg forms, and represents a discrete population, unique in its FL-3 intensity. The anaphylatoxin capture beads were incubated with standards (purified from human plasma) or test samples (sputum supernatant), washed, and then incubated with phycoerythrin-conjugated detection antibodies to form sandwich complexes. Two-color flow cytometric analysis was performed using a FACSCalibur flow cytometer (Becton Dickinson Immunocytometry Systems, San Jose, CA). Data were acquired and analyzed using Becton Dickinson Cytometric Bead Array CBA software. Anaphylatoxine concentrations were determined from the standard curves, plotting anaphylatoxine calibrator concentration versus FL-2 mean fluorescence intensity.

Statistical Analyses
Differences in C3a, C4a, and C5a levels in induced sputum between the study groups and the control subjects were assessed by a Mann-Whitney U test. The strength of association between variables was obtained by the Spearman rank-order method. Probability values of P < 0.05 were accepted as significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Results of the counts of inflammatory cells in induced sputum of patients with COPD, patients with asthma, and control subjects are presented in Table 1. TNNC was significantly increased in patients with asthma, compared with those with COPD (P = 0.003) and healthy control subjects (P = 0.002). The percentages of eosinophils in induced sputum were significantly increased in patients with asthma (P = 0.002) and those with COPD (P = 0.02), compared with healthy control subjects. The concentrations of C5a were significantly elevated in both patients with COPD (median, range; 1.636 ng/ml, 0.278–6.582 ng/ml; P = 0.007) and in patients with asthma (median, range 1.293 ng/ml, 0.259–5.895 ng/ml; P = 0.002) compared with a control group (median, range 0.353 ng/ml, 0.036–1.145 ng/ml) (Figures 1 and 2). In the COPD group, C5a concentration was significantly negatively correlated with the diffusion capacity of lungs (r = –0.71, P = 0.035) (Figure 3). There was no significant difference in concentrations of C3a and C4a in induced sputum between patients with COPD (median, range; C3a: 0.663 ng/ml, 0.467–8.693 ng/ml, C4a: 10.616 ng/ml, 2.620–21.394 ng/ml), those with asthma (median, range; C3a: 4.590 ng/ml, 0.452–99.222 ng/ml, C4a: 5.591 ng/ml, 0.475–79.740 ng/ml) or healthy control subjects (median, range; C3a: 2.131 ng/ml, 0.143–50.144 ng/ml, C4a: 1.983 ng/ml, 0.017–54.048 ng/ml) (Figure 4).


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  		TABLE 1. Cell counts in induced sputum of subjects with COPD, subjects with asthma, and control subjects

 


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  		Figure 1. Representative data for cytometric bead array anaphylatoxine measurement in induced sputum of control subjects (A) and subjects with COPD (B). Two-color dot plot FL-2 versus FL-3 presenting C4a, C3a, and C5a by three discrete FL-3 microparticle dye intensities distributed along the y-axis. FL2 presents the values for sample fluorescence intensities.

 


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  		Figure 2. C5a concentrations in induced sputum of subjects with COPD (n = 7), subjects with asthma (n = 10) and control subjects (n = 12). The horizontal solid bars indicate the median value for each group. C5a concentrations were significantly elevated in patients with COPD (P = 0.007) and in those with asthma (P = 0.002) compared with a control group.

 


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  		Figure 3. The regression curve for the correlation of C5a concentration in induced sputum with diffusion capacity of the lungs in patients with COPD (n = 7). We found a significant negative correlation between C5a concentration and diffusion capacity of the lungs (r = –0.71, P = 0.035).

 


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  		Figure 4. (A) C3a and (B) C4a concentrations in induced sputum of subjects with COPD (n = 7), subjects with asthma (n = 10), and control subjects (n = 12). The horizontal solid bars indicate the median value for each group.

 
There was no significant correlation between the level of airflow obstruction, TNNC, numbers of eosinophils, neutrophils, macrophages, or lymphocytes, or subject age and C3a, C4a, or C5a concentrations in induced sputum in any of the three groups.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study was the first to evaluate concentrations of C3a, C4a, and C5a, with their desArg forms, in the airways of patients with COPD. The results showed that C5a levels in the induced sputum of the COPD group were significantly higher compared with the healthy control subjects. Previous studies showed that component C5 can be synthesized in the lungs by alveolar type II cells (8) and converted to the biologically active fragment C5a via classical or alternative pathways of complement activation or directly by neutral tryptase released from mast cells and pulmonary macrophages (6, 7). Considering the evident local C5 production and activation, and the fact that we measured anaphylatoxins in the induced sputum of subjects without any signs of systemic inflammation, the elevated levels of C5a are more likely due to the local complement production than due to increased spillover from systemic circulation. Because the patients with COPD in our study all had a history of heavy smoking (mean 37 ± 6.2 pack-years), cigarette smoke could be one of the factors responsible for C5a elevation in the induced sputum of these subjects. Previous studies found cigarette smoke to be one of the activators of the alternative pathway (21–24), and in vitro cigarette smoke has been shown to cause an increase in the population of human bronchial epithelial cells (HBECs) that express C5a receptors (25).

C5a was shown to exacerbate inflammation through different pathways. It was identified as a potent chemotactic factor for many inflammatory cells (neutrophils, mast cells, basophils, eosinophils, and lymphocytes) (9–12, 26) and is able to enhance degranulation of eosinophils, mast cells, and basophils, as well as cytokine release from macrophages (15, 16, 27, 28). Therefore, persistently elevated intrapulmonary C5a may also be responsible for the extent of emphysematous changes in patients with COPD by maintaining chronic inflammation and subsequent release of cytokines and elastolytic encymes from activated inflammatory cells. DLCO strongly correlates with the degree of anatomic emphysema in smokers (29, 30), and we found a significant negative correlation between C5a levels and DLCO values in patients with COPD, which could further suggest the involvement of C5a in developing emphysema.

Regarding C3a and C4a levels, we detected no significant difference between patients with COPD and healthy control subjects. C3a was mainly investigated on asthmatic models, and many features of asthma are consistent with C3a (3–5). C4a is a byproduct of the classical pathway of complement activation. In vitro or animal studies have shown C4a to be considerably less active than C3a and C5a in terms of spasmogenic and vascular activities (31), and there is no evidence that C4a is chemotactic for inflammatory cells (32, 33). The results of previous studies found lower serum levels of the inactive components C3 and C4 in patients with COPD compared with healthy subjects (1, 2).

In patients with asthma, Van de Graaf and colleagues found increased levels of C3a in BALF compared with a healthy control group (34). Krug and coworkers showed a significant upregulation of anaphylatoxins C3a and C5a in BALF of patients with asthma after segmental allergen provocation (18). Similarly, Humbles and coworkers found upregulated C3a levels after allergen provocation (13). In vitro or on different animal models, both C5a and C3a anaphylatoxins were shown to promote smooth muscle contraction, mucus hypersecretion and recruitment, and degranulation of inflammatory cells, which are the features observed in asthma exacerbation (3, 13, 14). We found significantly elevated levels of C5a in the induced sputum of patients with asthma compared with the control subjects. Surprisingly, we did not detect any significant difference in C3a concentrations between patients with asthma and healthy control subjects, probably due to a stable phase of a disease in our patients with no evident exacerbation in the last weeks before the sample collection.

In conclusion, our study was the first one to evaluate C5a concentrations in the induced sputum of patients with COPD. The results of our study show significantly elevated levels of C5a in the induced sputum of patients with COPD and those with asthma. C5a concentrations in patients with COPD significantly negatively correlated with DLCO. These results suggest the involvement of C5a in the pathogenesis of COPD and asthma.


   Acknowledgments
 
The authors are grateful to all volunteers who participated in this study. They thank the Slovenian Ministry of Science, who funded part of this work.

Received in original form November 4, 2003

Received in final form January 27, 2004


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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