Intratracheal pulmonary ventilation keeps tracheal tubes clean without impairing mucociliary transport.

BACKGROUND: Intratracheal pulmonary ventilation (ITPV) is a form of tracheal gas insufflation through a reverse thrust catheter that facilitates expiration and enhances CO2 removal. Tracheas of sheep mechanically ventilated for 3 days with gas delivered through the reverse-thrust catheter remained free of secretions, without suctioning. It was hypothesized that: 1) The expiratory flow from the lungs, combined with continuous cephalad flow from the reverse-thrust catheter keeps endotracheal tubes clean; and 2) tracheal mucus velocity is not impaired by ITPV. METHODS: A model trachea connected to a test lung and to a ventilator, via an 8-mm endotracheal tube, was used. Inspiratory and expiratory peak flow velocities and the movement of mucus in the model trachea and in the endotracheal tube were measured during conventional mechanical ventilation and ITPV. Tracheal mucus velocity was measured radiographically, using tantalum discs as markers, in seven intubated sheep ventilated for one hour with volume-controlled ventilation, and with ITPV. One millilitre Evans Blue dye was introduced into the trachea, to visualize mucus transport into the endotracheal tube. RESULTS: Peak expiratory flow velocity exceeded peak inspiratory flow velocity by 100% during ITPV. During volume-controlled ventilation, flow velocities were equal. During ITPV, there was slow, then rapid cephalad movement of mucus in the model trachea, 0.5 cm distal to the tip of the endotracheal tube, the velocity increasing once mucus entered the endotracheal tube. During volume-controlled ventilation, no movement of mucus was found. Baseline tracheal mucus velocity was equal during volume-controlled ventilation and ITPV. Secretions stained with Evans Blue dye entered the endotracheal tube and were rapidly expelled from within the endotracheal tubes during ITPV; only traces of mucus were found in two sheep during volume-controlled ventilation. CONCLUSION: The enhanced expiratory flow during ITPV expels secretions from the endotracheal tube through entraining of mucus at the tip of the endotracheal tube. Tracheal mucus velocity is not influenced by ITPV.

A role for CD99 in T cell activation.

The function of the T cell surface protein CD99 was investigated in human CD4(+) peripheral T cells. Crosslinking of the CD99 molecule using anti-CD99 mAbs in the presence of anti-CD3 Ab resulted in a marked enhancement of proliferation. CD99 coligation also enhanced CD25 expression and early markers of T cell activation, CD69 and CD40L. Ligation of CD99 resulted in the pronounced tyrosine phosphorylation of an approximately 29-kDa protein suggesting that a specific CD99-induced signal transduction pathway may exist. Simultaneous costimulation with anti-CD99 and anti-CD28 Abs appeared to have additive effects on CD40L expression while CD99 ligation had no effect on CD2-mediated T cell induction of CD40L expression. These results demonstrate that CD99 signal transduction can deliver effective costimulatory signals to T cells.

Regulation of CD40L expression by cyclic AMP: contrasting proinflammatory and inhibitory actions.

CD40L expression is well recognized to be of critical importance in initiation of the immune response. Because cAMP mediates actions of bronchodilators commonly used in asthma, the effects of cAMP in regulating the immune response are of major importance. Cyclic AMP was found to either inhibit or markedly increase CD40L expression dependent upon the mechanisms of T cell activation. Cyclic AMP inhibited CD40L expression induced by TCR activation. In contrast, cAMP enhanced CD40L induced by CD2-mediated T cell activation or by calcium-dependent mechanisms. While neither CD28 costimulation nor exogenous IL-2 or IL-4 prevented cAMP inhibition in TCR activated cells, addition of calcium ionophore to TCR activation prevented any inhibitory effects and caused cAMP to increase CD40L expression. Actions of cAMP to increase CD40L expression appeared independent of PKC and were not a reflection of generalized cellular activation since neither CD25 nor CD69 expression was affected. The markedly contrasting actions of cAMP to decrease or increase CD40L expression, an important control point in the immune response, could be relevant to actions of commonly used medications including bronchodilators.

CD40 is functionally expressed on human breast carcinomas: variable inducibility by cytokines and enhancement of Fas-mediated apoptosis.

The CD40 molecule, a member of the TNF receptor gene family, has been intensively studied with respect to regulation of B cell proliferation and survival. Although CD40 is also expressed on carcinoma cell lines, information concerning the biological function of CD40 on cells of epithelial origin is limited. In this study we detected constitutive CD40 on human breast carcinoma cell lines and an increase in CD40 expression following treatment with cytokines IL-1alpha and IFN-gamma. CD40 ligation was also found to increase MHC II expression in cells pretreated with IFN-gamma. In contrast to normal B cells, where CD40 signaling provides a potent survival signal, we observed that CD40 ligation in breast carcinoma cells results in growth inhibition and enhanced susceptibility to Fas-mediated apoptosis. Enhanced apoptosis appears to be attributable, at least in part, to an up-regulation of Fas expression caused by CD40 ligation. These results suggest a potentially important role for CD40 in breast tumor biology.

Oncostatin M-specific receptor mediates inhibition of breast cancer cell growth and down-regulation of the c-myc proto-oncogene.

Human oncostatin M (OM) is a M(r) 28,000 glycoprotein that has been shown to regulate cell proliferation and differentiation. The biological activities of OM can be mediated by two different heterodimeric receptor complexes, the leukemia inhibitory factor (LIF)/OM shared receptor and the OM-specific receptor. In this study, we have examined the growth-regulatory effect of OM on 10 breast cancer cell lines derived from human tumors. The cellular proliferation of seven of these breast cancer cell lines was inhibited by OM. The three cell lines that did not respond to OM treatment lacked the expression of OM receptors. The growth-inhibitory activity of OM is examined further in the H3922 breast cancer cell line, which expresses the high-affinity OM receptor at a relatively higher level. We found that the cellular proliferation of H3922 cells was induced strongly by extrogenous epidermal growth factor (EGF), EGF-like factor, and basic fibroblast growth factor. The proliferative activities of these growth factors can be abolished totally by cotreatment of H3922 cells with OM. Treatment of H3922 cells with OM for 24 h did not block EGF binding or the induction of EGF receptor tyrosine phosphorylation. This finding suggests that OM interferes with the mitogenic signal at steps distal to the EGF receptor. Examination of proto-oncogene expression demonstrated that OM down-regulates the c-myc gene in H3922 cells. The biological effects reported herein are not shared by the OM-related cytokines interleukin 6 or LIF, as demonstrated by the inability of these proteins to inhibit cell growth or modulate c-myc gene expression in breast cancer cells. Additionally, the high-affinity binding of labeled OM cannot be displaced by LIF. Together, these data suggest that OM is a growth inhibitor for breast cancer cells. The inhibitory activity is mediated predominantly through the OM-specific receptor, and activation of this receptor abrogates growth factor stimulation and down-regulates the c-myc proto-oncogene.

Glucocorticoid-mediated inhibition of RANTES expression in human T lymphocytes.

The chemokine RANTES has been implicated in the pathogenesis of allergic inflammatory diseases including asthma and rhinitis which are frequently treated with glucocorticoids. We observed that dexamethasone dramatically inhibited RANTES mRNA expression dose dependently in anti-CD3 activated Hut-78 T cells and human PBMCs. Inhibition of RANTES expression did not appear to be secondary to IL-2 inhibition and required binding to the intracellular glucocorticoid receptor. The down-regulation of RANTES expression by glucocorticoids in T cells may directly contribute to the efficacy of these agents in suppressing cellular infiltration and to their anti-inflammatory properties.