Bronchoalveolar lavage (BAL) leukocyte-secreted cytokines are considered to be important mediators of the inflammatory and allergic reactions in the lung. This study examines quantitative changes in the level of tumor necrosis factor-alpha (TNF alpha) and interferon-gamma (IFN gamma) production in BAL cell cultures derived from patients (n = 11) with bronchial asthma. The secretion of TNF alpha and IFN gamma was determined in intact (unstimulated) and phytohemagglutinin/phorbol myristate acetate (PHA + PMA)-stimulated BAL leukocyte cultures and compared with that in control cultures. In all patients studied, the background and PHA + PMA-induced secretion of TNF alpha and IFN gamma was significantly (p < 0.001) higher than that in parallel control cultures. In contrast to BAL cell preparations, the capacity of TNF alpha and IFN gamma secretion by patients' peripheral blood mononuclear cells (PBMC) did not differ from that of control subjects. High spontaneous release of TNF alpha and IFN gamma by patients' BAL leukocytes, but not PBMC, suggest that in the pathophysiology of bronchial asthma, these cytokines may act as local pathogenic agents in the lung.

Thermal injury-associated specific immune deficiency occurs despite indicators of systemic activation of the lymphoid compartment. We investigated the possibility that postburn immune failure and T cell activation are casually related through activation-induced (apoptotic) cell death. The relationship between the cellular immune response and cell mortality was examined in cultures of peripheral blood mononuclear cells (PBMC) from 14 immunosuppressed patients with extensive burns (35-90% total body surface area). Impaired cellular immunity coincided with significantly reduced cell viability as ascertained by propidium iodide staining and dye reduction assays. Following stimulation with the mitogenic lectin, phytohemagglutinin (PHA), the majority of DNA in patient cultures was fragmented, suggesting the occurrence of apoptotic cell death. Even without stimulation a portion of patient cells was apoptotic as indicated by oligonucleosomal bands on agarose gel electrophoresis. Exogenous interleukin-2 or phorbol ester markedly reduced constitutive as well as PHA-induced DNA fragmentation. In situ demonstration of DNA strand breaks in freshly isolated patient PBMC, by a TdT-based labeling technique, confirmed that a larger fraction (up to 60%) of circulating lymphocytes was undergoing apoptosis on the periphery. These novel observations suggest that apoptosis may play a major role in thermal injury-related cellular immunodeficiency.

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The production of interferon-alpha(IFN-alpha), IFN-beta, and IFN-gamma by airway leukocytes from induced sputa (IS) of asthmatics was investigated. The groups consisted of 32 corticosteroid-free asthmatics (A), with 13 nonsmokers (nS) and 19 smokers (S), and 30 inhaled corticosteroid-treated asthmatics (cA) with 14 nS and 16 S. The control healthy group (H) comprised 11 nS and 15 S. The levels of IFNs in media from cultures of IS leukocytes were assessed by ELISA. The cells of the smokers produced lower amounts of IFN-alpha than those of nonsmokers in groups H, A, and cA (p = 0.0417, 0.0002, 0.0495, respectively) and significantly higher amounts of IFNbeta than nonsmokers in groups H (p = 0.0044) and cA (p = 0.0007). No differences in the levels of IFN-gamma were observed between S and nS in groups H (p = 0.8148), A (p = 0.8339), and cA (p = 0.0722). In the entire group of smokers, smoking indices correlated negatively with IFN-alpha (R(S) = -0.4374, p = 0.0006), and positively with IFN-beta (R(S) = 0.4239, p = 0.0009). There was no correlation with IFN-gamma (R(S) = 0.0471, p = 0.7004). The results suggest that production of IFNs by the airway leukocytes of cA may be modified by cigarette smoking toward deficient production of IFN-alpha and excess production of IFN-beta, which may have implications in the pathophysiology of asthma.

We have found that many synthetic selenoorganic compounds, including ebselen, have immunotropic activity. These studies were designed to assess the effect of the analog of ebselen bis[2-pyridyl (2-carbamoyl) phenyl]diselenide (AE-22) on human leukocytes that may express various activation states. The cells were obtained from bronchoalveolar lavage (BAL) cells of patients with various inflammatory lung diseases. The AE-22-treated BAL cells from patients with bronchial asthma (n = 6) and with small cell lung cancer (SCLC) (n = 6) were compared with these in the peripheral blood leukocytes (PBL) from the same donors. The control group comprised 5 patients who underwent diagnostic examination and were free of any cancer or concomitant diseases. Secretion of TNF-alpha, IL-6, and IFN-gamma was considered as a marker of BAL or PBL cell activation. Different response of the cells and various effects of AE-22 were observed in relation to the origin and functional state of leukocytes. It was established that AE-22 can induce TNF-alpha, IL-6, and IFN-gamma in a dose-dependent manner in BAL cells and PBL isolated from healthy individuals. However, BAL cells were found to be less reactive than PBL as cytokine producers. In contrast, AE-22 had no effect on BAL cells obtained from patients with lung cancer, which were found to be hyporeactive to phytohemagglutinin and bacterial lipopolysaccharide and did not produce TNF-alpha, IL-6, or IFN spontaneously. The spontaneous release of cytokines by BAL cells from bronchial asthma patients, but not by PBL from the same individuals, was significantly (p < 0.01) higher than that from the cultures of healthy control subjects. The high secretion of cytokines by the locally activated BAL cells was significantly (p < 0.01) reduced after administration of AE-22. The results suggest that AE-22 has immunomodulatory activity. AE-22 can downregulate the hyporeactive BAL cells from asthmatics, but it appears to be inactive in BAL cells of cancer patients who can tolerate the cytokine inducers.