Granulomatous bronchiolitis of Crohn's disease successfully treated with inhaled budesonide.

A 39-year-old white woman with longstanding Crohn's disease presented with the rare complication of granulomatous bronchiolitis. Rapid resolution after inhaled budesonide is highlighted, as this is the first case described in the literature successfully treated without the need for systemic therapy. This less toxic approach to therapy is warranted in granulomatous bronchiolitis of Crohn's disease to avoid unwanted side effects of steroids and infliximab.

Differences in the response times of pages originating from the ICU.

STUDY OBJECTIVES: To determine whether the type of paging system causes significant differences in the response time by physicians to their pages in an ICU setting. DESIGN AND SETTING: Prospective cohort study performed in the ICU of two university-affiliated hospitals. All pages were classified by several different variables, including the type of paging system: direct paging if a nurse or hospital operator could directly place the page, or indirect paging if a nurse or hospital operator was required to contact the physician's office or a private answering service who would then independently contact the physician. The main outcome measure was physicians' response time, in minutes, to pages originating from the ICU. RESULTS: During a 100-day period, 402 pages were sent and answered by 166 different physicians (87 attending physicians and 79 housestaff/physician assistants). The median response time for all pages was 3 min with a 25 to 75% quartile of 1 to 8 min. Twenty-five percent of the pages placed through an indirect system were associated with a response time of >/= 29 min. In a multivariate model with the response time dichotomized at >/= 15 min ("slow") or < 15 min ("adequate"), pages placed through an indirect system were answered significantly more slowly than pages placed through a direct system (p < 0.001; odds ratio, 4.36; 95% confidence interval, 2.05 to 9.29). Pages answered in an adequate amount of time were also associated with a significantly higher degree of overall nursing satisfaction with the care delivered by the physician in response to the specific page when compared with pages answered in a "slow" manner (p < 0.001). CONCLUSIONS: Physicians who use an indirect paging system are significantly slower in their response to ICU pages when compared with physicians who utilize a direct paging system. These results may lead to improvements in paging systems used by physicians who care for patients in an ICU setting.

Cytokine-cytokine synergy and protein kinase C in the regulation of lung fibroblast leukemia inhibitory factor.

Studies were undertaken to characterize the cytokines and cytokine-cytokine interactions that stimulate human lung fibroblast leukemia inhibitory factor (LIF) production and the mechanisms of these regulatory effects were investigated. Unstimulated fibroblasts did not produce significant amounts of LIF, whereas recombinant interleukin-1 alpha (rIL-1 alpha), transforming growth factor-beta (TGF-beta), and recombinant tumor necrosis factor (rTNF) were dose-dependent stimulators of LIF production. TGF-beta and rIL-1 alpha also interacted in a synergistic fashion to further increase LIF elaboration. Under all conditions alterations in LIF production were associated with comparable alterations in LIF mRNA accumulation. The kinetics of mRNA induction, however, differed with rIL-1-induced LIF mRNA being readily detected after 2 h, TGF-beta 1 induction peaking after 16-24 h, and the induction caused by rIL-1 alpha plus TGF-beta 1 being most prominent after 2-4 h and decreasing with additional incubation. Protein synthesis was not required for LIF induction. In addition, even though A23187 was an effective stimulator of LIF production, the calmodulin antagonists W-7 and trifluoperazone dichoride (TFP) did not significantly alter the LIF-stimulatory effects of IL-1 and TGF-beta. PKC did appear to play an important role in this induction, however, since LIF was induced by PMA and cytokine induction of LIF production was markedly diminished by chronic phorbol ester preincubation, staurosporine, and H-7, but not by HA1004. These studies demonstrate that 1) rIL-1, TGF-beta, TNF, agents that increase intracellular calcium and agents that activate PKC, stimulate lung fibroblast LIF production; 2) rIL-1 and TGF-beta interact in a synergistic fashion to further increase fibroblast LIF production; and 3) rIL-1 and TGF-beta stimulate lung fibroblast LIF production via a pretranslational activation pathway that is largely PKC-dependent and protein synthesis-, cyclic nucleotide-, and calmodulin-independent. Cytokine-stimulated LIF production may play an important role in homeostasis and repair in the human lung.

Epithelial interleukin-11. Regulation by cytokines, respiratory syncytial virus, and retinoic acid.

Interleukin-11 (IL-11) is a pleiotropic cytokine with effects that overlap with IL-6. To determine if IL-11 is produced by epithelial cells, we determined whether human alveolar A549 cells and airway 9HTE cells produce IL-11. We also determined whether retinoic acid (RA) altered this IL-11 production. Unstimulated cells produced low levels of IL-11, while IL-1, transforming growth factor (TGF-beta 1), and respiratory syncytial virus (RSV) stimulated IL-11 protein production and mRNA accumulation in a time- and dose-dependent fashion. IL-1 and TGF-beta 1 also interacted in a synergistic, and presumedly transcriptional, fashion since they augmented A549 cell IL-11 protein production and mRNA accumulation without altering IL-11 mRNA half-life. In contrast, IL-4 only weakly stimulated, and IL-7, hepatocyte growth factor, and herpes simplex virus Type 2 did not stimulate, IL-11 production. RA did not alter the IL-11 production of unstimulated or RSV infected cells. It did, however, inhibit rIL-1-stimulated and synergistically augment TGF-beta-stimulated IL-11 production. Thus, IL-1, TGF-beta, and RSV stimulate epithelial-like cell IL-11 production, and RA regulates these inductive processes in a stimulus-specific fashion.

IL-1 and transforming growth factor-beta regulation of fibroblast-derived IL-11.

IL-11 and IL-6 are fibroblast-derived cytokines with overlapping biologic properties. To determine whether IL-11 and IL-6 are similarly regulated, we characterized the effects of rIL-1 and TGF-beta (beta 1 and beta 2) on human lung fibroblast IL-11 production and compared this regulation with that of IL-6. Unstimulated fibroblasts did not produce significant amounts of IL-11, whereas rIL-1 alpha and TGF-beta were dose-dependent stimulators of IL-11 protein production, mRNA accumulation, and gene transcription. rIL-1 alpha and TGF-beta also interacted in a synergistic fashion to further increase IL-11 protein production and mRNA accumulation. The effects of rIL-1 and TGF-beta individually were not altered by the cyclic nucleotide-dependent protein kinase inhibitor HA1004, protein kinase C (PKC) inhibition with staurosporine, or chronic phorbol ester preincubation, or the calmodulin antagonists W7 and TFP. The effects of rIL-1 alpha and TGF-beta in combination were also unaltered by HA1004, staurosporine, and chronic phorbol ester exposure. A23187, however, did induce IL-11 mRNA accumulation and W7 and TFP did reverse the synergistic stimulation caused by rIL-1 and TGF-beta in combination. In contrast with the regulation of IL-11, TGF-beta did not effectively stimulate IL-6 mRNA accumulation, rIL-1 alpha was a more potent stimulator of IL-6 than IL-11 production, and rIL-1-induced IL-6 mRNA accumulation was augmented by W7 and TFP. These studies demonstrate that: 1) rIL-1, TGF-beta, and agents that increase intracellular calcium stimulate lung fibroblast IL-11; 2) the IL-11 stimulatory effects of rIL-1 and TGF-beta are, at least partially, transcriptionally mediated and are the result of signal transduction pathways that are largely PKC, cyclic nucleotide, and calmodulin independent; and 3) rIL-1 and TGF-beta interact in a synergistic fashion to further increase fibroblast IL-11 production and that this synergy is mediated by a largely PKC- and cyclic nucleotide-independent and calmodulin-dependent activation pathway. Importantly, they also demonstrate that rIL-1 and TGF-beta stimulate lung fibroblast IL-6 and IL-11 production via distinct and differentially regulatable activation pathways.