Hiroyuki Yoshimine

Essential contribution of monocyte chemoattractant protein-1/C-C chemokine ligand-2 to resolution and repair processes in acute bacterial pneumonia

Neutrophil infiltration is the first step in eradication of bacterial infection, but neutrophils rapidly die after killing bacteria. Subsequent accumulation of macrophage lineage cells, such as alveolar macrophages (AMs), is essential to remove dying neutrophils, which are a source of injurious substances. Macrophage lineage cells can promote tissue repair, by producing potential growth factors including hepatocyte growth factor (HGF). However, it remains elusive which factor activates macrophage in these processes. Intratracheal instillation of Pseudomonas aeruginosa caused neutrophil infiltration in the airspace; subsequently, the numbers of total AMs and neutrophil ingested AMs were increased. Bronchoalveolar lavage (BAL) fluid levels of monocyte chemoattractant protein (MCP)-1/CC chemokine ligand-2 (CCL2), a potent macrophage-activating factor, were increased before the increases in the number of AM ingesting neutrophils and HGF levels in BAL fluid. Immunoreactive MCP-1 proteins were detected in alveolar type II epithelial cells and AMs only after P. aeruginosa infection. The administration of anti-MCP-1/CCL2 Abs reduced the increases in the number of AM-ingesting neutrophils and HGF levels in BAL fluid, and eventually aggravated lung tissue injury. In contrast, the administration of MCP-1/CCL2 enhanced the increases in the number of AM ingesting neutrophils and HGF levels in BAL fluid, and eventually attenuated lung tissue injury. Furthermore, MCP-1/CCL2 enhanced the ingestion of apoptotic neutrophils and HGF production by a mouse macrophage cell line, RAW 267.4, in a dose-dependent manner. Collectively, MCP-1/CCL2 has a crucial role in the resolution and repair processes of acute bacterial pneumonia by enhancing the removal of dying neutrophils and HGF production by AMs

Fourteen-member macrolides promote the phosphatidylserine receptor-dependent phagocytosis of apoptotic neutrophils by alveolar macrophages

ABSTRACT An inflammation of the airway of patients with diffuse panbronchiolitis (DPB), is characterized by dense neutrophil infiltration. Resolution of the inflammation can be achieved by the removal of apoptotic neutrophils by human alveolar macrophages (AM) without liberating neutrophil proteases in the airway. To understand clinical efficacy for the treatment of DPB by 14- or 15-member macrolides, their effects on the phagocytosis of apoptotic neutrophils by AM were examined. Treatment of AM with erythromycin (ERY) or clarithromycin at clinically achievable levels significantly increased the levels of phagocytosis of apoptotic neutrophils. A serum factor was not essential for the enhancement by these 14-member macrolides. Of the antibiotics tested, these effects were specific for the 14-member macrolides and a 15-member macrolide, azithromycin, but not for the 16-member macrolides, clindamycin or β-lactam antibiotics. The enhanced phagocytosis of apoptotic neutrophils by ERY had no effect on the levels of interleukin-8 or tumor necrosis factor alpha production by lipopolysaccharide-stimulated AM after phagocytosis of the apoptotic neutrophils. The increased phagocytosis of apoptotic neutrophils by ERY was also found to be phosphatidylserine receptor-dependent for AM. These data indicate a novel anti-inflammatory action of 14-member and 15-member macrolides, and suggest that such antibiotics achieve clinical efficacy for patients with DPB, in part, through enhancing the nonphlogistic phagocytosis of apoptotic neutrophils by AM.

Drug-resistant genes and serotypes of pneumococcal strains of community-acquired pneumonia among adults in Japan

Background:  A high frequency of drug‐resistant pneumococci has been reported in Asian countries. Few data on the drug‐resistance or serotype of pneumococcal strains responsible for community‐acquired pneumonia (CAP), however, are available for the past two decades in Japan.

Decreased Serum Opsonic Activity against Streptococcus pneumoniae in Human Immunodeficiency Virus—Infected Ugandan Adults

Type-specific immunoglobulin G (IgG) to pneumococcal capsular polysaccharide (CPS) and opsonic activity against Streptococcus pneumoniae were evaluated in serum samples from 36 Ugandan adults with community-acquired pneumonia and 58 asymptomatic Ugandan adults with or without human immunodeficiency virus type 1 (HIV-1) infection. The levels of serum IgG to CPS were significantly higher in HIV-1-infected subjects than in HIV-uninfected subjects. Serum samples from HIV-1-infected subjects that had lower IgG titers demonstrated higher opsonic activity against type 3 (titers of 7) and type 9 (titers of 7-11) pneumococcal strains. Plasma HIV-1 load also correlated inversely with serum opsonic activity against these strains, and peripheral blood CD4+ lymphocyte numbers also tended to correlate with serum opsonic activity in asymptomatic HIV-1-infected adults. Our findings suggest that the opsonic activity of type-specific IgG is impaired in the serum of HIV-1-infected African adults, which may expose them to a serious risk of invasive pneumococcal infections.

Induction of opsonophagocytic killing activity with pneumococcal conjugate vaccine in human immunodeficiency virus-infected Ugandan adults.

The levels of IgG determined by ELISA may have limited relevance in human immunodeficiency virus (HIV)-infected adults because of non-functional antibodies. 58 HIV-1-infected and 29 HIV-uninfected Ugandan adults were immunized with conjugate vaccine (CV) followed by polysaccharide vaccine (PV) after a 2-month interval, and the opsonophagocytic killing (OPK) titers against serotype 4 or 14 pneumococcal strains as well as the levels of serotype-specific IgG in sera were determined. Significant increases were found in the OPK titers and IgG levels for both serotypes after CV vaccination irrespective of HIV status. Increases in IgG levels and OPK titers were largely dependent on the CD4(+) cell counts, except for increases in the IgG levels for serotype 4. The proportions with serum OPK titer equal to or greater than 8 were 0-4.3% for serotype 4 and 26.7-42.9% for serotype 14 before vaccination, but the proportions increased up to 43.3-86.2% for serotype 4 and 63.3-96.6% for serotype 14 in all three groups 2 months after CV vaccination. The serum OPK titers remained at levels higher than the pre-vaccination level for at least 8 months after CV vaccination. A single dose of CV could afford some protective immunity in HIV-infected African adults before the introduction of antiretroviral therapy.

Adult community‐acquired pneumonia caused by macrolide resistant Mycoplasma pneumoniae

A 28‐year‐old woman with community‐acquired pneumonia was treated with sulbactam/ampicillin and clarithromycin, but failed to show any improvement after 4 days. The antibiotic regimen was changed to pazufloxacin and rapid clinical improvement was seen. Mycoplasma pneumoniae was identified as the causative agent, and adenine (A) to guanine (G) mutation at position 2063 in domain V of the 23S rRNA was noted in the isolate. The minimum inhibitory concentration of macrolide antibiotics, including clarithromycin, of this isolate was greatly elevated.

Vaccine Effectiveness against Medically Attended Laboratory-Confirmed Influenza in Japan, 2011–2012 Season

The objective of this study was to estimate influenza vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza during the 2011–2012 season in Japan using a test-negative case-control study design. The effect of co-circulating non-influenza respiratory viruses (NIRVs) on VE estimates was also explored. Nasopharyngeal swab samples were collected from outpatients with influenza-like illnesses (ILIs) in a community hospital in Nagasaki, Japan. Thirteen respiratory viruses (RVs), including influenza A and B, were identified from the samples using a multiplex polymerase chain reaction. The difference in VE point estimates was assessed using three different controls: ILI patients that tested negative for influenza, those that tested negative for all RVs, and those that tested positive for NIRVs. The adjusted VE against medically attended, laboratory-confirmed influenza using all influenza-negative controls was 5.3% (95% confidence interval [CI], −60.5 to 44.1). The adjusted VEs using RV-negative and NIRV-positive controls were −1.5% (95% CI, −74.7 to 41) and 50% (95% CI, −43.2 to 82.5), respectively. Influenza VE was limited in Japan during the 2011–2012 season. Although the evidence is not conclusive, co-circulating NIRVs may affect influenza VE estimates in test-negative case-control studies.

Fourteen-Member Macrolides Suppress Interleukin-8 Production but Do Not Promote Apoptosis of Activated Neutrophils

ABSTRACT A 14-member macrolide was found to inhibit interleukin-8 (IL-8) synthesis in lipopolysaccharide-stimulated neutrophils but did not accelerate apoptosis in activated neutrophils. These data suggest that 14-member macrolides achieve clinical efficacy for chronic airway diseases partly by suppressing IL-8 production by activated neutrophils, but not by enhancing apoptosis in these cells.

Significant Reduction of Nosocomial Pneumonia after Introduction of Disinfection of Upper Airways Using Povidone-Iodine in Geriatric Wards

We investigated the efficacy of disinfection of the upper airway using povidone-iodine against nosocomial pneumonia in geriatric wards. Cases of nosocomial pneumonia were retrospectively analyzed between January 1991 and March 1995 in geriatric wards (190 beds). Moreover, the relationship concerning methicillin-resistant Staphylococcus aureus (MRSA) isolates between patient and environment was investigated using pulsed-field gel electrophoresis (PFGE) with the SmaI restriction enzyme. The incidence of nosocomial pneumonia decreased significantly (p < 0.05). Major causative organisms of nosocomial pneumonia were MRSA and Pseudomonas aeruginosa, which significantly decreased. PFGE studies showed that the patterns of MRSA isolates show a strong association between patient and environment. Our study indicates that disinfection of the upper airways by povidone-iodine is very important in the prevention of nosocomial pneumonia in geriatric wards.

Expression of Chemokine Receptors on CD4+ T Cells in Peripheral Blood from HIV-Infected Individuals in Uganda

CXCR4, a coreceptor for T cell (T)-tropic HIV-1, is preferentially expressed on naive T cells, whereas CCR5, a coreceptor for macrophage (M)-tropic HIV-1, is preferentially expressed on previously activated memory T cells and the Th1 subset of CD4+ T cells. CCR4 is preferentially expressed on the Th2 subset of CD4+ T cells. A cross-sectional flow cytometry study was conducted to evaluate the expression of CXCR4, CCR5, and CCR4 on the peripheral blood CD4+ T cells from African HIV-1-infected and uninfected Ugandan adults. The plasma viral load in HIV-1-infected individuals was also examined. Upregulation of CCR4 and CCR5 expression but no decrease in CXCR4 expression on CD4+ T cells were obtained in peripheral blood from African adults with progression of the disease. Plasma HIV-1 viremia significantly and inversely correlated with the peripheral CD4+ T cell count but did not correlate with the degree of CCR4 and CCR5 expression on the peripheral CD4+ T cells in HIV-1-infected individuals. Our present data suggest an increase in percentage of activated memory CD4+ T cells in the advanced stage of HIV-1 infection among African adults. There was no evidence of a Th1 to Th2 shift in terms of chemokine receptor expression profile with advancing disease in the peripheral blood of these subjects.