Krzysztof Kowal

Enhanced frequencies of CD14++CD16+, but not CD14+CD16+, peripheral blood monocytes in severe asthmatic patients

CD16+ monocytes are expanded in various inflammatory conditions. Recently it was reported that CD16+ monocytes can be divided into two subsets with contrasting potential of modulating inflammatory responses, namely CD14++CD16+ and CD14+CD16+ monocytes. Here, we characterized and quantified CD14++CD16+ and CD14+CD16+ monocyte subsets in asthmatic patients in the context of severity of disease and different treatment options. Subjects included seventeen severe asthmatics and eighteen moderate asthmatics treated with moderate-to-high doses of inhaled glucocorticosteroids (GCS), twenty nine steroid-naive mild asthmatics and fifteen healthy controls. First, we demonstrated that CD14++CD16+ monocytes, in contrast to CD14+CD16+ monocytes, present significantly higher expression of anti-inflammatory molecule CD163. The frequency of CD14++CD16+, but not CD14+CD16+ monocytes, was significantly higher in patients with severe asthma as compared to mild and moderate asthmatics. However, the frequency of both CD16+ monocyte subsets did not correlate directly with exhaled nitric oxide levels. Short-term administration of oral GCS in patients with exacerbations resulted in a preferential decrease of CD14+CD16+ monocytes. Our study indicates that CD14++CD16+ and CD14+CD16+ monocyte subsets in asthmatics are differentially modulated by both the inflammatory process and GCS treatment.

Platelet activation in allergic asthma patients during allergen challenge with Dermatophagoides pteronyssinus.

Background Animal models of allergic asthma indicate that intravascular platelet activation is necessary for the development of allergen‐induced chronic airway inflammation.

CD163 and its role in inflammation

Mononuclear phagocytes represent a heterogeneous population of cells with individual subpopulations exerting different pro- or anti-inflammatory functions. CD163 is a monocyte/macrophage specific marker expressed predominantly on cells which possess strong anti-inflammatory potential. The expression of CD163 is strongly induced by anti-inflammatory mediators such as glucocorticoids and interleukin-10, while being inhibited by pro-inflammatory mediators such as interferon-gamma. CD163-expressing mononuclear phagocytes, as well as soluble CD163, may both take part in downregulating an inflammatory response. It seems, therefore, that CD163 may be an interesting target for therapeutic modulation of the inflammatory response.

ß Thromboglobulin and platelet factor 4 in bronchoalveolar lavage fluid of patients with systemic sclerosis

Objective: To evaluate concentrations of the platelet activation markers β thromboglobulin (BTG) and platelet factor 4 (PF4) in bronchoalveolar lavage fluid (BALF) from patients with systemic sclerosis with and without scleroderma interstitial lung disease (SLD). Methods: BTG and PF-4 were measured by enzyme immunoassay in BALF from 37 patients with systemic sclerosis. Controls were 10 healthy subjects. BALF was collected during routine bronchoscopy from the right middle lobe. SLD was diagnosed by high resolution computed tomography of the lungs. Results: BTG was detected in 11 of the patients with systemic sclerosis (29.7%) and PF4 was found in eight (21.6%). Mean (SD) concentrations of BTG and PF4 in BALF from patients with detectable levels of these platelet activation markers were 106.9 (69.8) and 35.2 (17.4) IU/ml, respectively. The BTG:PF4 ratio was more than 2:1, indicating in vivo release. Both markers were found exclusively in patients with SLD. SLD patients with detectable platelet activation markers had a significantly shorter disease duration than those with undetectable BTG/PF4. Conclusions: The study provides evidence that activation of blood platelets takes place within the lungs of patients with SLD and may contribute to the development of lung fibrosis.

Exhaled Nitric Oxide in Evaluation of Young Adults with Chronic Cough

Background. Bronchial asthma (A) is frequently diagnosed in patients with chronic cough. The study was conducted to determine whether an evaluation of fractional exhaled nitric oxide (FeNO) concentration can be used as a screening test for asthma in young adults with chronic cough (CCP). Methods. The study was performed on 540 (mean age 26.5; range 18–45 years), nonsmoking young CCP. All patients had resting spirometry within normal limits and no abnormalities on chest radiographs. Skin prick tests with common aeroallergens, bronchial provocation challenge with histamine, and evaluation of FeNO concentration were performed in all patients. One hundred healthy, nonsmoking, nonatopic subjects were used as control subjects (HC). Results. Asthma (A) was diagnosed in 178 CCP (32.96%). Other frequent diagnoses included rhinitis/sinusitis (R) and gastroesophageal reflux (GERD). The median FeNO concentration in A (86 ppb; 95% CI 72 to 94,5 ppb) was significantly greater than in R (37 ppb; 95% CI 35,6 to 42,9 ppb; p < 0.0001), GERD (14,8 ppb; 95%CI 13.3 to 16.2 ppb; p < 0.0001), or in HC (13 ppb; 95%CI 11 to 15 ppb; p < 0.0001). Significant correlation was found between logFeNO and bronchial reactivity expressed as logPC20 (r = −0.529; 95%CI −0.616 to −0.429; p < 0.0001), but even stronger correlation was demonstrated between logFeNO and peripheral blood eosinophilia (r = 0.757; 95%CI 0.717 to 0.792). Receiver Operator Characteristic (ROC) curve analysis revealed that CCP can be screened for A by measuring FeNO concentration. Using 40 ppb as a cut-off value for the FeNO concentration, the specificity 82.6% and sensitivity 88.3% can be achieved. Conclusion. In clinical practice, assessment of FeNO concentration can be used as a screening test for asthma in young adults who have chronic cough.

The −675 4G/5G plasminogen activator inhibitor-1 promoter polymorphism in house dust mite-sensitive allergic asthma patients

Background:  Plasminogen activator inhibitor (PAI)‐1 plays an important role in inflammation and tissue remodeling. Recently, the −675 4G/5G PAI‐1 polymorphism has been linked with asthma.

Mechanisms of Disease: leukotrienes and lipoxins in scleroderma lung disease—insights and potential therapeutic implications

Scleroderma interstitial lung disease (SLD) is a leading cause of morbidity and mortality in patients with systemic sclerosis. Although the pathogenesis of SLD is not clear, excessive fibrosis and inflammatory cell infiltration are the main histologic features of this disorder. Leukotrienes and lipoxins are two functionally different classes of lipoxygenase-derived eicosanoids. Leukotrienes are potent proinflammatory mediators and directly and indirectly stimulate fibroblast chemotaxis, proliferation, and collagen synthesis. Lipoxins counter-regulate the proinflammatory actions of leukotrienes and activate resolution of the inflammatory response. In addition, lipoxins inhibit growth-factor-induced fibroblast proliferation and collagen synthesis. Studies using bronchoalveolar lavage have revealed that there is an overproduction of proinflammatory and profibrotic leukotrienes in the lungs of patients with SLD, and that leukotriene levels correlate with inflammatory indices within the lungs. Moreover, the increased levels of leukotrienes in these patients are not balanced by an upregulation of anti-inflammatory and antifibrotic lipoxins. Unopposed actions of leukotrienes might, therefore, induce chronic inflammation and fibrosis in the lungs of SLD patients. Accordingly, pharmacologic correction of a leukotriene–lipoxin imbalance using leukotriene inhibitors or lipoxin analogs might be a new approach to the treatment of SLD.

Plasminogen activator inhibitor-1 (PAI-1) and urokinase plasminogen activator (uPA) in sputum of allergic asthma patients.

Urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) have been associated with asthma. The aim of this study was to evaluate concentration of uPA and PAI-1 in induced sputum of house dust mite allergic asthmatics (HDM-AAs). The study was performed on 19 HDM-AAs and 8 healthy nonatopic controls (HCs). Concentration of uPA and PAI-1 was evaluated in induced sputum supernatants using ELISA method. In HDM-AAs the median sputum concentration of uPA (128 pg/ml; 95% CI 99 to 183 pg/ml) and PAI-1 (4063 pg/ml; 95%CI 3319 to 4784 pg/ml) were significantly greater than in HCs (17 pg/ml; 95%CI 12 to 32 pg/ml; p<0.001 and 626 pg/ml; 95%CI 357 to 961 pg/ml; p<0.001 for uPA and PAI-1 respectively). The sputum concentration of uPA correlated with sputum total cell count (r=0.781; p=0.0001) and with logarithmically transformed exhaled nitric oxide concentration (eNO) (r=0.486; p=0.035) but not with FEV1 or bronchial reactivity to histamine. On the contrary, the sputum PAI-1 concentration correlated with FEV1 (r=-0,718; p=0.0005) and bronchial reactivity to histamine expressed as log(PC20) (r=-0.824; p<0.0001) but did not correlate with sputum total cell count or eNO. The results of this study support previous observations linking PAI-1 with airway remodeling and uPA with cellular inflammation. Moreover, the observed effect of uPA seems to be independent of its fibrynolytic activity.

Differential expression of monocyte CD163 in single – and dual‐asthmatic responders during allergen‐induced bronchoconstriction

Background Mononuclear phagocytes play an important role in modulating inflammatory reactions in response to antigen challenge.

Serum levels of CD163 and TWEAK in patients with pulmonary arterial hypertension

BACKGROUND Inflammation may play a pivotal role in the pathogenesis of pulmonary arterial hypertension (PAH). We evaluated the concentrations of serum sTWEAK, its scavenger receptor sCD163 and sTWEAK/sCD163 ratio in patients with PAH. DESIGN The study enrolled 26 stable patients with PAH confirmed by right heart catheterization and 24 healthy volunteers matched for age, sex and body weight. All patients underwent transthoracic echocardiography, cardiopulmonary exercise test, 6-min walk test, measurement of lung diffusing capacity for the carbon monoxide (DLCO) and venous blood tests. Concentrations of sTWEAK and sCD163 were determined using ELISA kits. RESULTS The PAH patients were characterized by significantly higher median serum sCD163 levels (1072 vs 890ng/ml, p=0.04) together with lower serum sTWEAK concentrations (200 vs 278.1pg/ml, p=0.003) comparing to control subjects. sTWEAK/sCD163 ratio was therefore significantly lower in PAH group (0.18 vs 0.33, p=0.0005). No correlation was found between sTWEAK and sCD163 concentrations in both groups. We observed statistically significant inverse correlation between peak VO2 consumption and sCD163 concentrations (r=-0.52, p<0.05) and positive with sTWEAK/sCD163 ratio (r=0.45, p<0.05) in PAH group. Moreover, sTWEAK/sCD163 ratio positively correlated with % of predicted values of DLCO (r=0.42, p<0.05). CONCLUSIONS Patients with PAH present altered serum sTWEAK and sCD163 levels. The sTWEAK/sCD163 ratio appears to be a better indicator of the severity of PAH as compared to sTWEAK or sCD163 alone. The exact role of sCD163 or interaction between CD163 and sTWEAK in the initiation or progression of PAH as well as their potential prognostic significance remains to be established.