Naomi Hirata

Fibroproliferative changes on high-resolution CT in the acute respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational cohort study

Objectives To examine whether the extent of fibroproliferative changes on high-resolution CT (HRCT) scan influences prognosis, ventilator dependency and the associated outcomes in patients with early acute respiratory distress syndrome (ARDS). Design A prospective observational cohort study. Setting Intensive care unit in a teaching hospital. Participants 85 patients with ARDS who met American-European Consensus Conference Criteria and eligible criteria. Interventions HRCT scans were performed and prospectively evaluated by two independent observers on the day of diagnosis and graded into six findings according to the extent of fibroproliferation. An overall HRCT score was obtained by previously published method. Primary and secondary outcomes The primary outcome was 60-day mortality. Secondary outcomes included the number of ventilator-free days, organ failure-free days, the incidence of barotraumas and the occurrence of ventilator-associated pneumonia. Results Higher HRCT scores were associated with statistically significant decreases in organ failure-free days as well as ventilator-free days. Multivariate Cox proportional hazards model showed that the HRCT score remained an independent risk factor for mortality (HR 1.20; 95% CI 1.06 to 1.36; p=0.005). Multivariate analysis also revealed that the CT score had predictive value for ventilator weaning within 28 days (OR 0.63; 95% CI 0.48 to 0.82; p=0.0006) as well as for an incidence of barotraumas (OR 1.61; 95% CI 1.08 to 2.38; p=0.018) and for an occurrence of ventilator-associated pneumonia (OR 1.46; 95% CI 1.13 to 1.89; p=0.004). A HRCT score <210 enabled prediction of 60-day survival with 71% sensitivity and 72% specificity and of ventilator-weaning within 28 days with 75% sensitivity and 76% specificity. Conclusions Pulmonary fibroproliferation assessed by HRCT in patients with early ARDS predicts increased mortality with an increased susceptibility to multiple organ failure, including ventilator dependency and its associated outcomes.

The role of cysteinyl leukotrienes in the pathogenesis of asthma: Clinical study of leukotriene antagonist pranlukast for 1 year in moderate and severe asthma

Clinical studies have shown that pranlukast (Ono Pharmaceutical Co., Osaka, Japan) is effective for mild and moderate asthma. However, it is not well known that pranlukast is also effective on moderate and severe persistent asthma in the long term. We studied the effect of pranlukast on moderate and severe asthmatics by evaluating the change of peak expiratory flow (PEF) and therapeutic scores for 1 year before and during pranlukast therapy. We gave pranlukast 225 mg twice daily orally to 25 patients who were receiving more than 400 μg/day beclomethasone inhalation and β2 stimulant inhalation with or without oral corticosteroid. Pranlukast increased PEF more than 10 L/min in 14 patients in the first 4 weeks. In these 14 patients, 10 patients continued to monitor PEF and kept asthma diaries for 1 year. We compared the data for 1 year before and during the pranlukast therapy. During the pranlukast therapy, PEF significantly increased, puffs of β2 stimulant inhalation significantly decreased. The incidence of oral corticosteroid rescue therapy reduced, and the mean daily dose of oral corticosteroid decreased; however, they were not statistically significant. During treatment with pranlukast, no side effect was observed. From these results, we suggest that pranlukast is effective for more than half of the moderate and severe persistent asthmatics, and that the effectiveness continues for more than 1 year.

The role of substance P release in the lung with esophageal acid

To investigate whether tachykinins are released in the airways by stimulating the esophagus, airway plasma extravasation induced by intraesophageal hydrochloric acid (HCl) in the presence or absence of the neutral endopeptidase (NEP) inhibitor phosphoramidon and the neurokinin-1-receptor antagonist FK888 was studied in anesthetized guinea pigs. Airway plasma extravasation also was studied in the presence of the NEP inhibitor in guinea pigs pretreated with capsaicin or bilateral vagotomy. Propranolol and atropine were used in all animals to block adrenergic and cholinergic nerve effects. Airway plasma leakage was evaluated by measuring extravasated Evans blue dye. One normal HCl infusion into the esophagus significantly increased plasma extravasation in the trachea. Phosphoramidon significantly potentiated plasma extravasation induced by HCl infusion into the esophagus in the trachea and main bronchi, and FK888 significantly inhibited extravasation in a dose-related manner. In capsaicin-treated animals, airway plasma extravasation was completely inhibited even in the presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilaterally vagotomized animals. These results suggest that locally acting substances are released by intraesophageal HCl stimulation that cause airway plasma extravasation. These substances are generated through activation of neural pathways, including some that traffic through the vagus nerves that link the esophagus or airways.

CD8 and CD103 Are Highly Expressed in Asthmatic Bronchial Intraepithelial Lymphocytes

Background: Although characteristics of intraepithelial lymphocytes (IELs) in mucosal immunity have been well defined in the intestine, bronchial IELs have been little investigated. Recently, we showed that bronchial IELs have a distinct function that partly resembles that of intestinal IELs; however, surface antigen expression of bronchial IELs and the relationship of that expression to airway disease have not been studied. Methods: We analyzed phenotypic profiles of human bronchial IELs and lamina propria lymphocytes (LPLs) by double-staining immunohistochemistry using full-thickness bronchial specimens (10 nonasthmatic controls and 7 asthmatics) from lung resections. Results: In controls, the percentage of CD4+ cells was lower, and the percentage of CD8+ cells was higher in IELs compared to LPLs (CD4: median 50.0% in IELs vs. 65.9% in LPLs, p = 0.01; CD8: 50.9% in IELs vs. 34.4% in LPLs, p = 0.007). The percentage of cells positive for CD103 (αE-integrin) was higher in IELs than that in LPLs (median 60.1% in IELs vs. 16.9% in LPLs; p < 0.001). In IELs from asthmatics, these characteristics were particularly significant (CD4: median 26.2%, p = 0.008; CD8: 79.8%, p = 0.007; CD103: 76.2%, p = 0.019; all compared with IELs from nonasthmatics). Conclusions: These results suggest that human bronchial IELs have roles distinct from subsets of other lymphocytes, and that CD8+ cells and CD103+ cells have potentially important functions in the bronchial epithelium.

Tachykinin antagonist FK224 inhibits neurokinin A‐, substance P‐ and capsaicin‐induced human bronchial contraction

Summary— To determine the roles of endogenously released tachykinins (substance P [SP] and neurokinin A [NKA]) in the human bronchial tissues, we studied the effects of tachykinin antagonist FK224 on bronchial smooth muscle contraction induced by SP, NKA and capsaicin in an organ bath. FK224 (10−6 M and 10−5 M, respectivly) significantly inhibited NKA‐induced contraction and 10−5 M FK224 shifted the dose‐response curve to more than one log unit higher concentration. Because SP‐ and capsaicin‐induced contractions were small, we pretreated the tissues with the neutral endopeptidase inhibitor phosphoramidon (10−5 M), which inhibits degradation of exogenous tachykinins in order to potentiate the contractions. FK224 (10−5 M) significantly inhibited SP‐induced contraction and it shifted the dose‐response curves to about one log unit higher concentration. FK224 (10−5 M) also significantly inhibited capsaicin‐induced contraction and it shifted the dose‐response curves to more than one log unit higher concentration. In contrast, FK224 (10−5 M) did not affect on acetylcholine‐, histamine‐, and leukotriene D4‐induced contraction. These results suggest that FK224 is a tachykinin receptor antagonist in the human bronchial smooth muscle, and that capsaicin‐induced contraction is due to endogenously released tachykinin‐like substances in the human bronchus.

T Cells of Atopic Asthmatics Preferentially Infiltrate Into Human Bronchial Xenografts in SCID Mice

T cells play an important role in the pathogenesis of bronchial asthma. However, it is not completely known how circulating lymphocytes infiltrate into the airways of asthmatic patients. Because SCID mice are unable to reject xenogenic transplants, many xenotransplant models using various human tissues have been developed. Therefore, to examine the interaction between bronchi and T lymphocytes of asthma, it may be possible to use the human bronchial xenograft and PBMC xenograft in SCID mice. We transplanted human bronchi into the subcutaneum of SCID mice and i.p. injected PBMCs that were obtained from patients with atopic asthma, atopic dermatitis and rheumatoid arthritis, and normal subjects (asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice). There was no difference in the percentage of CD3-, CD4-, CD8-, CD25-, CD45RO-, CD103-, and cutaneous lymphocyte Ag-positive cells in PBMCs among the patients with asthma, dermatitis, rheumatoid arthritis, and normal subjects, and CD3-positive cells in peripheral blood of asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice. The number of CD3-, CD4-, and CD8-positive cells in the xenografts of asthmatic huPBMC-SCID mice was higher than those of dermatitis, rheumatic, and normal huPBMC-SCID mice. IL-4 mRNA and IL-5 mRNA were significantly higher in the xenografts of asthmatic huPBMC-SCID mice than those in the xenografts of normal huPBMC-SCID mice, but there were no significant differences in the expressions of IL-2 mRNA or IFN-γ mRNA between them. These findings suggest that T cells, especially Th2-type T cells, of asthmatics preferentially infiltrate into the human bronchi.

Human bronchial intraepithelial T cells produce interferon-γ and stimulate epithelial cells

Intraepithelial lymphocytes (IELs) can be identified among epithelial cells in systemic mucosal tissues. Although intestinal IELs play a crucial role in mucosal immunity, their bronchial counterparts have not been well studied. The purpose of this study was to determine the immunological functions of human bronchial IELs, which interact directly with epithelial cells, unlike lamina propria lymphocytes (LPLs). We isolated successfully bronchial IELs and LPLs using a magnetic cell separation system from the T cell suspensions extracted from bronchial specimens far from the tumours of resected lungs. Human bronchial IELs showed an apparent type 1 cytokine profile and proliferated more actively in response to CD2 signalling than did bronchial LPLs. CD8+ IELs were identified as the most significant sources of interferon (IFN)‐γ. Human bronchial epithelial cells constitutively produced the T cell growth factors interleukin (IL)‐7 and IL‐15, and levels of those factors increased when cells were stimulated by IFN‐γ. Bronchial epithelial cells expressed cell surface proteins CD58 and E‐cadherin, possibly enabling adhesion to IELs. In summary, human bronchial IELs have immunological functions distinct from bronchial LPLs and may interact with epithelial cells to maintain mucosal homeostasis.

Dyspnoea and hyperventilation induced by synthetic progesterone chlorpromadinone acetate for the treatment of prostatic hypertrophy

We describe a 74‐year‐old patient with dyspnoea and tachypnoea induced by chlorpromadinone acetate, a synthetic progesterone used to treat prostatic hyperplasia. The dyspnoea, tachypnoea and hypocapnia improved after discontinuing the chlorpromadinone acetate. It is important to recognize that synthetic progesterones can cause dyspnoea and hyperventilation.