Hepatocyte growth factor levels in Legionella pneumonia: a retrospective study.

BACKGROUND: Hepatocyte growth factor (HGF) is known to be involved in the resolution of pulmonary inflammation and repair of acute lung injury. Legionella pneumonia is sometimes complicated by acute lung injury. Our study aimed to determine the role of serum HGF levels in Legionella pneumonia. METHODS: Sera from patients with Legionella pneumonia (42 cases), other bacterial pneumonia (33 cases), pulmonary tuberculosis (19 cases), and normal controls (29 cases) were collected. The serum HGF levels for each serum sample were determined by sandwich ELISA. Clinical and laboratory data were collected by reviewing the medical charts. RESULTS: Serum HGF levels were higher in patients with Legionella pneumonia than in those with other bacterial pneumonia, pulmonary tuberculosis, and controls. The HGF levels were compared with white blood cell counts, C-reactive protein, Alanine amino-transferase, and lactate dehydrogenase (LDH). The HGF levels were correlated to serum LDH levels. Moreover, serum HGF levels were significantly higher in non-survivors than in survivors. CONCLUSIONS: HGF levels increased in severer pneumonia caused by Legionella, suggesting that HGF might play a significant role in the Legionella pneumonia.

[A case of drug-induced pneumonitis due to levofloxacin and kampo medicine].

A 55-year-old woman was admitted to our hospital because of dyspnea on exertion. Hypoxemia and restrictive ventilatory impairment were observed on admission. Chest radiographs showed diffuse patchy infiltration shadows in both lungs. We suspected drug-induced pneumonitis, because her history of fever seemed to be related to drug administration for sinusitis. Her symptoms and findings were gradually decreased by discontinuation of the drugs. Transbronchial lung biopsy specimens showed lymphocyte dominant infiltration in the alveolar septa and Masson bodies. Drug lymphocyte stimulation tests were positive for levofloxacin and shin-i-seihai-to, a kampo medicine. On the basis of these findings, we arrived at a diagnosis of drug-induced pneumonitis caused by these drugs.

Differential roles of Toll-like receptors 2 and 4 in in vitro responses of macrophages to Legionella pneumophila.

The role of Toll-like receptors (TLRs) in innate immunity to Legionella pneumophila, a gram-negative facultative intracellular bacterium, was studied by using bone marrow-derived macrophages and dendritic cells from TLR2-deficient (TLR2(-/-)), TLR4(-/-), and wild-type (WT) littermate (C57BL/6 x 129Sv) mice. Intracellular growth of L. pneumophila was enhanced within TLR2(-/-) macrophages compared to WT and TLR4(-/-) macrophages. There was no difference in the bacterial growth within dendritic cells from WT and TLR-deficient mice. Production of interleukin-12p40 (IL-12p40) and IL-10 after infection with L. pneumophila was attenuated in TLR2(-/-) macrophages compared to WT and TLR4(-/-) macrophages. Induction of IL-12p40, IL-10, and tumor necrosis factor alpha secretion from macrophages by the L. pneumophila dotO mutant, which cannot multiply within macrophages, and heat-killed bacteria, was similar to that caused by a viable virulent strain. There was no difference between the WT and its mutants in susceptibility to the cytopathic effect of bacteria. An L. pneumophila sonicated lysate induced IL-12p40 production by macrophages, but that of TLR2(-/-) macrophages was significantly lower than those of WT and TLR4(-/-) macrophages. Treatment of L. pneumophila sonicated lysate with proteinase K and heating did not abolish TLR2-dependent IL-12p40 production. Our results show that TLR2, but not TLR4, is involved in murine innate immunity against L. pneumophila, although other TLRs may also contribute to innate immunity against this organism.

In vitro and in vivo activity of olamufloxacin (HSR-903) against Legionella spp.

The activity of the fluoroquinolone olamufloxacin (HSR-903) against Legionella spp. was studied in vitro and in vivo. The olamufloxacin MIC at which 50% of isolates are inhibited (MIC50) for 81 different Legionella spp. strains (59 type strains and 22 clinical isolates) was 0.008 mg/L, which was identical to sparfloxacin, whereas the MIC50s for erythromycin, levofloxacin and ciprofloxacin were 0.25, 0.032 and 0.032 mg/L, respectively. Olamufloxacin and sparfloxacin (at 0.008 mg/L) inhibited intracellular growth and subsequent cytotoxicity of L. pneumophila 80-045 in J774.1 macrophages, whereas levofloxacin and ciprofloxacin did not, at the same concentration. When olamufloxacin was given to the infected guinea pigs orally (5 mg/kg of body weight), peak levels in the lung were 3.02 mg/kg at 2 h post-administration, with a half-life of 3.41 h and an AUC0-12 of 12.31 mg.h/kg. The 2 day post-infection bacterial burden of the lung in the animals treated with olamufloxacin (5 and 1.25 mg/kg given orally twice a day) was much lower than in those treated with levofloxacin (same dose as olamufloxacin) or erythromycin (10 mg/kg given orally twice a day). When treated with olamufloxacin (5 mg/kg given orally twice a day) for 7 days, 11 of 12 L. pneumophila-infected guinea pigs survived for 14 days post-infection, as did all 12 guinea pigs treated with levofloxacin (5 mg/kg given orally twice a day) for 7 days. In contrast, only two of 12 animals treated with erythromycin survived and 10 of 11 died in the physiological saline group. Olamufloxacin was as effective as levofloxacin in a guinea pig model of Legionnaires' disease. These data warrant further study of whether olamufloxacin is an option for the treatment of Legionella infections.

Legionella pneumophila pneumonia successfully treated with intravenous ciprofloxacin.

A 69-year-old man developed a cough and fever during treatment with corticosteroid (p.o. and external use) for erythroderma. Chest X-ray films revealed a consolidation shadow in the right upper lung field. Initial treatment with sulbactam sodium/ampicillin followed by imipenem/cilastatin was not effective. A urinary antigen test for Legionella was positive, making for a diagnosis of Legionella pneumonia. Intravenous treatment with ciprofloxacin (CPFX) was remarkably effective. His symptoms, chest X-ray and laboratory data rapidly improved after its initiation. Our findings strongly suggest that intravenous treatment with fluoroquinolones including CPFX should also be a first choice for Legionella pneumonia in Japan.

Induction of apoptosis of human macrophages in vitro by Legionella longbeachae through activation of the caspase pathway.

The cytotoxicity of the facultative intracellular bacterium, Legionella longbeachae, an important cause of legionellosis, was characterised. Apoptosis was induced in HL-60 cells, a human macrophage-like cell line, during the early stages of infection and induction of apoptosis correlated with cytotoxicity. Apoptosis was confirmed by agarose gel electrophoresis of fragmented DNA, surface exposure of phosphatidylserine and propidium iodide labelling of host cell nuclei. The involvement of macrophage infectivity potentiator (Mip) protein, a known virulence factor of L. longbeachae, was also examined. A mip mutant of L. longbeachae induced apoptosis of HL-60 cells but failed to multiply intracellularly, suggesting that intracellular replication of L. longbeachae is not essential for the induction of apoptosis of HL-60 cells. Furthermore, induction of apoptosis of L. longbeachae-infected macrophages was mediated by activation of the caspase pathway but might be independent of tumour necrosis factor-alpha- and Fas-mediated signal transduction pathways.