Koh Abe

Interleukin 1β, Tumor Necrosis Factor Alpha, and Interleukin 8 in Bronchoalveolar Lavage Fluid of Patients with Diffuse Panbronchiolitis: A Potential Mechanism of Macrolide Therapy

We measured the levels of interleukin (IL) 1 beta, tumor necrosis factor alpha, and IL-8 in bronchoalveolar lavage fluid (BALF) and sera of patients with diffuse panbronchiolitis (DPB) before and after administration of erythromycin or roxithromycin. The pretreatment levels of IL-1 beta and IL-8 were significantly higher in the BALF of patients with DPB than in the BALF of patients with sarcoidosis and controls. The tumor necrosis factor alpha level was also higher than in controls, but not statistically significant. There was a significant correlation between percentage of neutrophils and IL-8 level in the BALF of DPB patients (r = 0.509; p < 0.05) on the one hand and between IL-1 beta and IL-8 on the other (r = 0.476; p < 0.04). Treatment for 1-24 months significantly reduced BALF levels of IL-1 beta and IL-8 of DPB patients in parallel with a reduction in BALF neutrophils. The serum level of IL-8 of DPB patients was higher, albeit insignificant, than that of controls and significantly lower than that in the BALF of the same patients (p = 0.0088). Serum IL-1 beta was below the detection limit. In addition, the concentration of IL-8 in alveolar macrophages obtained from 2 volunteers before and after oral erythromycin administration also decreased ex vivo. Our results indicate that IL-8 induces the migration of neutrophils to inflammatory sites. It is possible that the macrolides impair production and/or secretion of these cytokines, ultimately reducing neutrophil accumulation in the airway.

High serum concentrations of surfactant protein A in usual interstitial pneumonia compared with non-specific interstitial pneumonia

Background: The pathological diagnosis of interstitial lung diseases (ILD) by surgical lung biopsy is important for clinical decision making. There is a need, however, to use serum markers for differentiating usual interstitial pneumonia (UIP) from other ILD. Surfactant protein (SP)-A, SP-D, KL-6, sialyl SSEA-1 (SLX), and sialyl Lewisa (CA19-9) are useful markers for the diagnosis and evaluation of activity of ILD. We have investigated the usefulness of these proteins as markers of UIP. Methods: Serum and bronchoalveolar lavage (BAL) fluid levels of the above five markers were measured in 57 patients with various forms of ILD (19 with UIP, 12 with non-specific interstitial pneumonia (NSIP), eight with bronchiolitis obliterans organising pneumonia (BOOP), and 10 with sarcoidosis), eight patients with the control disease (diffuse panbronchiolitis (DPB)), and nine healthy volunteers. Results: Serum levels of SP-A, SP-D, and KL-6 in patients with UIP and NSIP were significantly higher than in healthy volunteers. In particular, the serum levels of SP-A in patients with UIP were significantly higher than in patients with NSIP (p<0.0001, mean difference –58.3 ng/ml, 95% confidence interval –81.6 to –35.0), and BAL fluid levels of SP-D in patients with UIP were significantly lower than in patients with NSIP (p=0.01, mean difference 322.4 ng/ml, 95% confidence interval 79.3 to 565.5). Conclusion: Serum SP-A levels may be clinically useful as a biomarker to differentiate between UIP and NSIP.

Raised plasma concentrations of α-defensins in patients with idiopathic pulmonary fibrosis

Background: Neutrophils are thought to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Human neutrophils contain antimicrobial and cytotoxic peptides in the azurophil granules which belong to a family of mammalian neutrophil peptides named α-defensins. A study was undertaken to investigate the role of α-defensins in the pathogenesis of IPF. Methods: The concentrations of α-defensins (human neutrophil peptides (HNPs) 1, 2, and 3) in plasma and bronchoalveolar lavage (BAL) fluid of 30 patients with IPF and 15 healthy subjects were measured by radioimmunoassay. Results: The concentrations of α-defensins in plasma, but not in BAL fluid, were significantly higher in IPF patients than in controls. BAL fluid concentrations of interleukin (IL)-8 in patients with IPF, which were significantly higher than in controls, correlated with those of α-defensins. An inverse relationship was seen between plasma α-defensin levels and the arterial oxygen tension (Pao2) and pulmonary function (vital capacity (%VC), forced expiratory volume in 1 second (FEV1), and carbon monoxide transfer factor (%Tlco)) in patients with IPF. Plasma levels of α-defensins also correlated with the clinical course in IPF patients with an acute exacerbation. Immunohistochemically, positive staining was observed inside and outside neutrophils in the alveolar septa, especially in dense fibrotic areas. Conclusion: These findings suggest that α-defensins play an important role in the pathogenesis of IPF, and that the plasma α-defensin level may be a useful marker of disease severity and activity.

Th1-Th2 Cytokine Kinetics in the Bronchoalveolar Lavage Fluid of Mice Infected with Cryptococcus neoformans of Different Virulences

Th1 immune response plays an important role in protection against infection with Cryptococcus neoformans in mice. We investigated the effect of virulence of C. neoformans on cytokine production in the lung of a mouse model of pulmonary cryptococcosis. BALB/c mice were inoculated intratracheally with a high or low virulence strain of C. neoformans, followed by serial measurements of Th1 and Th2 cytokine concentrations in the bronchoalveolar lavage (BAL) fluid using appropriate enzyme‐linked immunosorbent assay kits. The number of colony‐forming units (CFU) increased with time, and all mice infected with the highly virulent strain were dead at 28 days after inoculation. In contrast, the number of microorganisms diminished with time in the mice infected with the low virulence strain during the 4‐week study. The numbers of neutrophils and lymphocytes in the BAL fluid paralleled those of CFU. High neutrophil counts were observed in the BAL fluid of mice infected with the highly virulent strain, while lymphocyte counts were increased only in the later part of the study in mice infected with the high and low virulence strains. The concentrations of Th2 cytokine, interleukin (IL)‐4 were significantly higher in mice infected with the highly virulent strain at days 14 and 21 of infection, whereas the level of Th1 cytokine, interferon‐gamma, was significantly higher in the latter strain at days 7 and 14. Our results suggest that strain‐specific difference in the organisms ability to induce (or evade) the host immune system contributes to the outcome of infection.

Increased Levels of Interleukin-18 in Bronchoalveolar Lavage Fluid of Patients with Idiopathic Nonspecific Interstitial Pneumonia

Background: Interleukin-18 (IL-18) is a proinflammatory cytokine that can induce interferon-γ (IFN-γ), and it plays an important role in T-helper 1 responses. Among idiopathic interstitial pneumonia (IIP), nonspecific interstitial pneumonia (NSIP) has an increased number of lymphocytes in bronchoalveolar lavage (BAL) fluid compared with usual interstitial pneumonia (UIP). However, the difference in their pathogenesis is unclear. Objective: The present study aims to investigate the roles of IL-18 in patients with idiopathic UIP and idiopathic NSIP. Methods: We measured the serum and BAL fluid (BALF) levels of IL-18 and IFN-γ in 22 patients with IIP (12 with UIP, 10 with NSIP) and 9 healthy volunteers. Results: Lymphocyte proportions in BALF were significantly higher in NSIP than in UIP and healthy subjects. No significant differences were observed in the serum IL-18 levels of all subjects, while the BALF levels of IL-18 in patients with NSIP were significantly higher than in patients with UIP (p < 0.005) and in healthy subjects (p < 0.005). Among all subjects, the levels of IL-18 in BALF correlated significantly with those in serum and the lymphocyte proportions in BALF. The serum IFN-γ levels of all subjects were below sensitivity, but there was significant reverse correlation between the levels of IFN-γ and the lymphocyte proportions in BALF. Conclusion: The lymphocytosis in BALF of patients with idiopathic NSIP and a part of idiopathic UIP might be associated with the high levels of IL-18.

Immunological competence and nutritional status in patients with lung cancer.

Abstract. The rate of infection in patients with malignant disease is significantly higher than in patients with benign disease. To investigate whether immunological competence is impaired in patients with lung cancer, we assessed neutrophil function (chemotaxis, phagocytosis, bacterial killing activity, and superoxide production), monocyte function (phagocytosis and killing activity), lymphocyte subsets using flow cytometry, and proliferation of lymphocytes stimulated by phytohemagglutinin, concanavalin A, and pokeweed mitogen. Studies were performed on 22 untreated patients with lung cancer and 21 age-matched healthy volunteers. Nutritional status was assessed by Niedermans nutritional index. In patients with lung cancer neutrophil chemotaxis, monocyte phagocytosis and killing, proliferation of lymphocytes stimulated by phytohemagglutinin and concanavalin A, but not pokeweed mitogen, and the number of natural killer cells were significantly lower than in healthy volunteers, whereas γδ T cells were increased (p < 0.05). The mean score on Niedermans nutritional index was worse in patients than in healthy volunteers (p < 0.001). Our results suggest that the impaired immunological competence and undernutrition may be among the mechanisms causing increased susceptibility to infection in patients with lung cancer.

Pulmonary alveolar proteinosis with lung squamous cell carcinoma

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by accumulation of periodic-acid-Schiff (PAS)-positive material in the alveolar space (1). Although the cause of this disease is unknown, functionally defective alveolar macrophages or defective clearance of intraalveolar surfactant re-uptake by type 2 pneumocytes have been proposed by some investigators (2,3). In this context, PAP has been reported as a complication of certain diseases such as tuberculosis, haematological malignancy, interstitial pneumonitis or AIDS (48). To our knowledge, we report the first case of extensively developed PAP coexisting with lung squamous cell carcinoma.

Effects of smoking cessation on gastric emptying in smokers.

Background Smoking cessation can lead to changes in appetite and weight gain in some patients; thus, smoking cessation may alter gastrointestinal motility. Effects of smoking cessation on gastric emptying in smokers have not been established. Aim This study sought to determine how smoking cessation affects gastric emptying in smokers. Methods Participant group comprised 53 habitual smokers and 12 healthy nonsmokers. Habitual smokers were treated for 2 months with transdermal nicotine patches. Gastric emptying was studied using 13C acetate breath tests at the beginning of the study, and at 1 week and 9 weeks after cessation of patch use. Maximal 13CO2 excretion time (Tmax), 13CO2 excretion half-life (T1/2), and parameters β and κ, representing initial and subsequent gastric-emptying phases, respectively, were determined using conventional formulae. Results Before smoking cessation, Tmax was reached significantly later in smokers (0.94±0.3 h, P=0.014) than in controls (0.89±0.1 h). At 1 week after the end of treatment, Tmax was significantly decreased (from 1.05±0.32 h to 0.72±0.64 h, P=0.003). T1/2 also tended to decrease, but not significantly. Although β was decreased significantly (from 2.46±0.40 to 2.17±0.58, P=0.022), κ was unchanged. However, by 9 weeks after the end of treatment, Tmax (1.28±0.69 h) had increased to levels seen before treatment. Conclusions Smoking cessation temporarily accelerates gastric emptying, and decreases in β suggest that initial-phase gastric emptying accelerates after smoking cessation. The temporary acceleration of gastric emptying after smoking cessation may be involved in the temporary increase in appetite and weight gain seen after smoking cessation.