Epidemiology of legionella pneumonia and factors associated with legionella-related mortality at a tertiary care center.

Legionella pneumophila is an important pathogen that may cause nosocomial and community-acquired pneumonia in patients with normal or altered immunity. The epidemiology of 40 cases of legionella pneumonia in patients hospitalized between 1986 and 1994 was studied. Fourteen patients (35%) were solid organ transplant recipients. The calculated annual incidence of L. pneumophila infection was highest among lung transplant recipients (2.07 cases per 1,000 transplant-years). There was a trend toward reduced mortality rates and less severe disease among transplant patients vs. nontransplant patients: mortality rate, 36% vs. 54%; incidence of intubation, 50% vs. 69%; rate of concurrent infections, 29% vs. 38%; and overall rate of complications, 86% vs. 96%; respectively. In a multivariate analysis, factors independently associated with an increased mortality rate were nosocomial acquisition, need for intubation, formation of lung abscess or cavitation, and presence of pleural effusion. Thus, despite differing host immune responses, the most important prognostic factors affecting the outcome of legionellosis are nosocomial acquisition and the development of pulmonary complications.

Modulation of human G-CSF receptor mRNA and protein in normal and leukemic myeloid cells by G-CSF and retinoic acid.

Granulocyte colony-stimulating factor (G-CSF) is produced by several cell types throughout the body and has a variety of effects on neutrophils and their precursors, which are mediated by binding to its receptor. It is not yet known what physiologic factors modulate G-CSF receptor mRNA expression in these cells. We studied the effect of G-CSF on freshly isolated neutrophils and bone marrow cells from normal human subjects and on myeloid leukemic cell lines. We found that G-CSF receptor mRNA levels were maintained by G-CSF in neutrophils but not in bone marrow cells. Of the leukemic cell lines tested, K562 and BV173, both of which contain the bcr-abl translocation, neither expressed G-CSF receptor mRNA. Whereas G-CSF did not affect mRNA levels for its receptor in myeloid leukemic cell lines, exposure of the acute promyelocytic cell line, NB4, to all-trans retinoic acid induced a striking increase in G-CSF receptor mRNA expression and resulted in increased G-CSF receptor surface expression. The effect of retinoic acid on G-CSF receptor mRNA on NB4 cells occurred early, before morphologic evidence of differentiation, and required protein synthesis. All-trans retinoic acid also upregulated G-CSF receptor mRNA in the myeloid leukemia cell line HL-60. Thus, maintenance of G-CSF receptor on neutrophils by G-CSF may extend the duration of ligand responsiveness. Furthermore, the ability of retinoic acid to up-regulate G-CSF receptor may account for the synergistic effect of G-CSF and retinoic acid in differentiation induction of acute promyelocytic leukemia.

Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases.

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that critically regulates the viability, proliferation, and differentiation of granulocytic precursors and the function of neutrophils by signaling through its receptor. Cloning of the human G-CSF receptor (G-CSFR) cDNA has demonstrated sequence homology with other members of the hematopoietic/cytokine receptor superfamily. G-CSF stimulates the appearance of phosphotyrosine proteins in several types of human and murine myeloid cells. Since the receptor does not possess intrinsic tyrosine kinase activity, we hypothesized that G-CSFR interacts with and activates cytosolic protein-tyrosine kinases (PTKs). In vitro protein kinase assay of human G-CSFR immunoprecipitates demonstrated at least two tyrosine phosphoproteins, pp55 and pp70. We observed that G-CSF activated p53/p56lyn, a Src-related PTK, and p72syk, a non-Src-related PTK. Lyn and Syk were recovered in anti-G-CSFR immunoprecipitates; Lyn was detected in the absence of ligand. In addition, upon G-CSF stimulation, Lyn coimmunoprecipitated with Syk. Analysis of the G-CSFR amino acid sequence revealed a potential receptor activation motif for Syk. On the basis of immunoprecipitation and sequence analysis data, we propose that the human G-CSFR forms a three-component signaling complex with Lyn and Syk. Their sequential recruitment into the G-CSFR signaling complex demonstrates the coordinated involvement of two PTKs with a member of the hematopoietic/cytokine receptor superfamily.

Human granulocyte colony-stimulating factor (G-CSF), the premier granulopoietin: biology, clinical utility, and receptor structure and function.

In summary, both G-CSF and GM-CSF have been identified, cloned, and produced for pharmacologic use in humans. While both G-CSF and GM-CSF have had significant impact in the treatment of neutropenic states, G-CSF appears to be more advantageous than GM-CSF in overall efficacy and paucity of side effects. Much has been discovered about the structure of the G-CSF receptor but further work is necessary to determine its mechanism of signal transduction. As our understanding of G-CSF signaling advances, the therapeutic impact of our knowledge about G-CSF biology will evolve from the current focus on enhancing its effects in hematologic and oncologic illnesses to decreasing its effects in inflammatory conditions where overexhuberant neutrophil infiltration and activation cause disease.