At the time of diagnosis, many sarcoidosis patients have no clinical indication for corticosteroid therapy, and prognostic parameters predicting deterioration are missing. In the present study, we investigated parameters derived from bronchoalveolar lavage (BAL) and serum in 77 patients with recently diagnosed sarcoidosis to test their predictive value. Patients were divided into a group with (Group A, n = 37) and a group without (Group B, n = 40) indications for therapy, and the course of the disease was evaluated after 5.7 +/- 0.4 mo. The CD4+/CD8+ lymphocyte ratio and percentage of BAL lymphocytes were of no predictive value. Release of tumor necrosis factor-alpha (TNF-alpha) from cultured alveolar macrophages (AM) was significantly increased in both groups (Group A = 1,872 +/- 428 pg/ml; Group B = 1,561 +/- 449 pg/ml) as compared with controls (220 +/- 37 pg/ml). In Group B, however, patients with a high level of TNF-alpha release had a significantly greater risk of disease progression than did those with normal TNF-alpha release (43.8% versus 8.3%, respectively). From the serologic parameters investigated, consisting of neopterin, angiotensin converting enzyme (ACE), and soluble interleukin-2 receptor (sIL-2R), only the last was of significant predictive value; 42.1% of sarcoidosis patients in Group B with a high level of sIL-2R experienced disease progression, whereas none of those with a normal level did. We conclude that TNF-alpha release and sIL-2R are suitable parameters for predicting disease progression in sarcoid patients who have no indication for therapy at the time of disease diagnosis.

The aim of the present study was to determine which bronchoalveolar lavage fluid (BALF) and serological parameters reflect the severity of newly diagnosed pulmonary sarcoidosis.Seventy-four previously untreated sarcoid patients were categorised into three groups: 10 patients with Löfgren9s syndrome, 51 patients with stable disease and 13 patients with progressing disease requiring systemic steroid treatment.Total BALF cell count, percentage of alveolar lymphocytes and lymphocyte CD4/ CD8 ratio were not associated with severity of disease. Interestingly, a significant increase in percentages of BALF neutrophils (5.2¡1.1%) and eosinophils (1.7¡0.6%) was observed in sarcoid patients with progressing disease. Elevated percentages of these two cell types were the only BALF parameters associated with a more frequent necessity for systemic steroid therapy. This association between an elevated percentage of BALF neutrophils and the necessity for steroid treatment was observed in advanced as well as early sarcoidosis (radiological types I and II). Serum levels of soluble interleukin-2 receptor and neopterin were significantly elevated in progressing disease compared to stable disease or Löfgren9s syndrome.The present results demonstrate that increased percentages of neutrophils (w3.0%) and eosinophils (w1%) in bronchoalveolar lavage fluid from newly diagnosed pulmonary sarcoidosis is associated with a significantly higher risk of necessity for steroid therapy and may be helpful markers of progressive disease. Furthermore, of the serological parameters investigated, only serum levels of soluble interleukin-2 receptor and neopterin were associated with disease severity. Eur Respir J 2003; 21: 407-413.

It has been shown that interleukin 8 (IL-8) is increased in bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF) and there is increasing evidence that it is involved in the pathogenesis of this disease. To date, no data are available as to whether IL-8 is elevated in sera of IPF patients. We obtained sera from 42 patients with IPF and 20 healthy controls at time of BAL. From 20 of 42 patients with IPF and 12 of 20 controls BALF was available, enabling us to measure IL-8 in serum and BALF of the same time point. IL-8 was significantly elevated in serum (54.7 +/- 7.5 pg/ml, p < 0.0001) and BALF (715.7 +/- 112.4 pg/ml, p < 0.0001) of patients with IPF compared with controls (IL-8 in serum, 5.2 +/- 0.8 pg/ml; IL-8 in BALF, 67.3 +/- 9.7 pg/ml). We observed a significant positive correlation between IL-8 levels in BALF and percentage of BALF neutrophils (p < 0.001) and between serum IL-8 and BALF IL-8 levels (p < 0.005) in patients with IPF. Consequently, the serum IL-8 level correlated positively with the percentage of BAL neutrophils (p < 0.01), indicating that it may reflect the degree of neutrophilic alveolitis in IPF. Furthermore, the serum IL-8 level showed a negative correlation with important indicators of impairment of lung function (DL(CO), TLC, VC) and PaO2. In conclusion, we were able to demonstrate that the degree of neutrophilic alveolitis in IPF is reflected by increased serum levels of IL-8 and we suggest that the serological assessment of IL-8 may provide a useful parameter for clinicians in monitoring patients with IPF.

Abstract. Ziegenhagen MW, Mü ller-Quernheim J

There is accumulating evidence that points to a role of serotonin (5-hydroxytryptamine [5-HT]) in the pathophysiology of asthma. Therefore, we analyzed the expression of serotoninergic receptors (5-HTR), its linkage to intracellular calcium homeostasis, and its influence on the production and secretion of IL-6, prostaglandin E(2), the CCL-Chemokine CCL5/Rantes, and the CXC-chemokines CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC in primary alveolar epithelial cells type II and the human lung cell lines A549 and BEAS-2B. Employing a PCR approach we were able to demonstrate mRNA expression of several 5-HTR, such as the heptahelical receptors 5-HTR1A, 5-HTR1B, 5-HTR1E, 5-HTR1F, 5-HTR2A, 5-HTR4, 5-HTR6, and 5-HTR7, as well as the ligand-gated ion channel 5-HTR3 in alveolar epithelial cells type II (AEC-II), A549, and BEAS-2B cells. To verify functional expression of 5-HTR subtypes, Ca(2+)-transients were analyzed. This enabled us to show that 5-HT induced an increase in intracellular calcium. Further experiments with isotype-selective receptor agonists allowed us to demonstrate that 5-HT induced calcium transients via activation of 5-HTR1, 5-HTR2, and 5-HTR3 in A549 and BEAS-2B cells. Moreover, we revealed that stimulation of 5-HTR1 and 5-HTR2 induced Ca(2+) mobilization from intracellular stores, whereas activation of 5-HTR3 induced Ca(2+) influx from the extracellular space. Functional studies indicated that activation of 5-HTR1B, 5-HTR1E/F, 5-HTR2, 5-HTR3, 5-HTR4, and 5-HTR7 regulated the release of the cytokine IL-6 and the CXC-chemokine CXCL8/IL-8. Our study shows that 5-HT stimulates different signaling pathways and regulates cytokine release in airway epithelial cells. In summary, our data implicate a pathophysiologic role of 5-HT in the asthmatic inflammatory responses in human airway epithelial cells.