Toshihide Hayano

Inflammatory cytokines in BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema.

To evaluate the pathogenesis of high-altitude pulmonary edema (HAPE), we performed bronchoalveolar lavage (BAL) and pulmonary hemodynamic studies in seven patients with HAPE at its early stage. We measured cell counts, biochemical contents, and concentrations of pro-inflammatory cytokines including interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF)-alpha and of anti-inflammatory cytokines including IL-1 receptor antagonist (ra) and IL-10 in the BAL fluid (BALF). All patients showed increased counts for total cells, alveolar macrophages, neutrophils and lymphocytes, and markedly elevated concentrations of proteins, lactate dehydrogenase, IL-1beta, IL-6, IL-8, TNF-alpha and IL-1ra. The levels of IL-1alpha and IL-10 were not increased. Patients also showed pulmonary hypertension with normal wedge pressure. Both the driving pressure obtained as pulmonary arterial pressure minus wedge pressure and the PaO2 under room air were significantly correlated with the concentrations of IL-6 and TNF-alpha in the BALF. These findings suggest that the inflammatory cytokines play a role at the early stage of HAPE and might be related to pulmonary hypertension.

Cytokines in bronchoalveolar lavage fluid in patients with high altitude pulmonary oedema at moderate altitude in Japan.

BACKGROUND: The precise mechanism of high altitude pulmonary oedema (HAPE) remains unclear. The purpose of this study was to evaluate the role of cytokines and P-selectin in the development of HAPE which occurred at moderate altitude in Japan. METHODS: The following cellular and biochemical markers and chemotactic cytokines were measured in the bronchoalveolar (BAL) fluid from four patients with HAPE at 2857-3180 m in the Japanese Alps: total proteins, albumin, lactate dehydrogenase (LDH), and interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor antagonist (ra), IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, and the soluble form of P-selectin. RESULTS: At admission there were significant increases in the levels of total cells, especially macrophages and neutrophils, total protein, albumin and LDH when compared with 13 healthy individuals. Furthermore, the levels of IL-1 beta, IL-6, IL-8, and TNF-alpha were also considerably increased but returned quickly to the normal ranges or were not detected after recovery. The levels of IL-1 alpha, IL-10, and P-selectin did not change. CONCLUSIONS: These results suggest that an inflammatory process almost identical with acute respiratory distress syndrome (ARDS) may occur in HAPE, but that these changes are transient and are not associated with any increase in P-selectin levels in the BAL fluid.

Churg-Strauss syndrome (allergic granulomatous angitis) presenting with ileus caused by ischemic ileal ulcer

Abstract: We report a rare case of Churg-Strauss syndrome (CSS) in a 41-year-old Japanese man with a history of middle-age onset of bronchial asthma who had severe abdominal pain. He presented with ileus caused by an annular ulcer of the ileum, attributable to mucosal ischemia resulting from necrotizing vasculitis of the mesenteric artery. He also had marked hypereosinophilia (51.5%), elevated serum IgE levels (34040 IU/ml), and generalized enlargement of the superficial cervical lymph nodes, containing eosinophilic granulomas. A stenotic lesion caused by an annular ulcer in the ileum was found and resected by laparotomy. Microscopic examination of the resected specimen revealed luminal narrowing or occlusion of small arteries in the ulcer base, subserosa, and mesenterium resulting from marked fibrotic intimal thickening with fragmentation or lack of the internal elastic lamina. These findings were diagnosed as vasculitis, scar stage. The postoperative course was uneventful, with the patient receiving a maintenance dose of prednisolone (10–15 mg/day) for 7 years subsequently. We must carefully diagnose and treat patients with middle-age onset asthma, because the symptom may be a lung manifestation of CSS, in which various organs including gastrointestinal tract are involved as a result of systemic necrotizing vasculitis.

Interferon-α elevates pulmonary blood pressure in sheep—the role of thromboxane cascade

We tested the effect of interferon-alpha on lung function to examine whether interferon-alpha causes some pathophysiological change in the lung. We prepared awake sheep with chronic lung lymph fistula, and measured the pulmonary hemodynamics, lung fluid balance and concentrations of prostanoid products. At 1 h after intravenous interferon-alpha administration (18 x 10(6) I.U.), pulmonary arterial pressure and pulmonary vascular resistance were significantly increased compared to the baseline values. The levels of thromboxane B2 in both plasma and lung lymph were increased concomitant with early elevation on pulmonary arterial pressure. In addition, OKY-046 [sodium-3[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid] (10 mg kg(-1)), a selective thromboxane synthase inhibitor, significantly prevented the interferon-alpha-induced pulmonary hypertension and thromboxane B2 production. While no evidence of increased pulmonary vascular leakage was observed. These findings suggest that a single infusion of interferon-alpha stimulates a thromboxane cascade and causes transient pulmonary hypertension. However, interferon-alpha itself or increased thromboxane A2 might not affect the pulmonary vascular permeability in sheep.

A 21-aminosteroid, U-74006F, attenuates endotoxin-induced lung injury in awake sheep.

The purpose of the present study was to examine the efficacy of U‐74006F, a 21‐aminosteroid, on lung dysfunction induced by endotoxaemia in awake sheep with lung lymph fistula and haemodynamic monitoring. We measured pulmonary haemodynamics, lung lymph balance, circulating leucocyte count, arterial blood gas tensions, and levels of thromboxane (Tx) B2 and 6‐keto‐prostaglandin (PG) F1α in plasma and lung lymph. We performed two experiments. In experiment 1 (n = 6), we intravenously infused Escherichia coli lipopolysaccharide endotoxin (1 μg/kg) over 30 min and observed the parameters over 5 h. In experiment 2 (n = 6), we pretreated sheep with an intravenous bolus of U‐74006F (2 mg/kg) 30 min before the infusion of endotoxin in the same manner of experiment 1, and continuously infused U‐74006F (0.5 mg/kg per h) over 5 h after the bolus during the experiment. The U‐74006F significantly suppressed the early pulmonary hypertension, the late increase in pulmonary permeability and the elevations of TxB2 and 6‐keto‐PGF1α levels in plasma and lung lymph during the early period following endotoxaemia, although the compound did not change the time course of leucocytopenia and hypoxaemia. These findings suggest that the administration of U‐74006F attenuates the lung dysfunction induced by endotoxaemia in awake sheep.

Neutrophils pretreated with granulocyte colony-stimulating factor (G-CSF) are not related to the severity of endotoxin-induced lung injury.

Neutrophils play an important role in mediating acute lung injury that is characteristic of adult respiratory distress syndrome. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase neutrophil counts and to enhance their biological functions. This study investigated the effects of neutrophils pretreated with G-CSF on endotoxin-induced lung injury in conscious sheep. Nineteen sheep were chronically instrumented with a lung lymph fistula and vascular catheters for monitoring. Sheep were randomly allocated into three groups: group 1-sheep were infused only with endotoxin; group 2-G-CSF (250 micrograms/day) was administered intravenously for 5 days prior to endotoxin; and group 3-G-CSF (125 micrograms) was administered just before endotoxin. In each group, sheep received E. coli endotoxin (1 microgram/kg) for 30 min and observations were made for 5 h after endotoxin administration. Circulating leukocyte counts before endotoxin markedly increased in group 2 and significantly decreased in group 3, when compared with the level in group 1 (9700 +/- 900 (SEM) in group 1, 49,900 +/- 10,000 in group 2, and 3600 +/- 600/microL in group 3). In each group, circulating leukocyte counts significantly decreased 1 h after endotoxin administration and then returned to baseline values. However, there were no significant differences in either pulmonary hemodynamic or lung lymph responses to endotoxin among the groups. The results indicate that G-CSF does not adversely affect physiologic responses of the lung to endotoxin in sheep.

Effect of post-treatment with granulocyte colony-stimulating factor on endotoxin-induced lung injury in sheep.

We administered a bolus of G-CSF (250 micrograms/body) just after the infusion of endotoxin (1 microgram/kg) in awake sheep with chronic lung lymph fistula to examine the effect of post-treatment with G-CSF on endotoxin-induced lung injury. We measured pulmonary hemodynamics, lung lymph flow, and concentrations of thromboxane B2 and 6-keto-prostaglandin F1 alpha in plasma and lung lymph. In the G-CSF post-treated group, the pulmonary arterial pressure, pulmonary vascular resistance, and lung lymph flow did not significantly increase in the late period (3-5 h after endotoxin infusion). The arterial oxygen gas tension in the late period was higher in the G-CSF post-treated sheep than in those that received only endotoxin. Although the level of thromboxane B2 in plasma significantly increased at 1 h after endotoxin, the lung lymph flow did not increase much in the G-CSF post-treated group. We conclude that post-treatment with G-CSF instead attenuates the degree of pulmonary vascular leakage on endotoxin-induced lung injury and increased thromboxane B2, the principle metabolite of thromboxane A2, may not exacerbate the injury in awake sheep.

Pharmacokinetic evaluation of (glycolato-O,O')diammine platinum(II) in lung lymph in sheep.

The pharmacokinetics of (glycolato‐O, O′)diammine platinum(II) (254‐S), especially the distribution and behavior in the lung lymph in sheep, was investigated and compared with that of cis‐diammine‐dichloroplatinum(II) (CDDP). The blood and lung lymph fluid were collected from the carotid artery and a lung lymph fistula, respectively, in conscious sheep following intravenous infusion of 100 mg/body of 254‐S and CDDP for 30 min. The concentrations of these platinum complexes were measured by using atomic absorption spectrometry. We analyzed the data using an anatomically based model including part of the lymphatic circulation. The ultrafilterable platinum of 254‐S showed much larger area under the curve (AUC) and transfer rate constants than that of CDDP, even though the mean residence times were the same. The total platinum showed the opposite pharmacokinetic behavior. In anesthetized sheep, when lung tissue samples were obtained by biopsy at the same times as those of blood and lung lymph sampling after infusion of these drugs, 254‐S distributed in lung tissue appeared to move more easily into lung lymph than CDDP, which tended to be retained in lung tissue. These differences in pharmacokinetic behavior between 254‐S and CDDP seemed to be caused by differences in their strength of protein binding, the association constants of 254‐S for plasma and lymph protein were much less than those of CDDP. From these results, 254‐S may have favorable therapeutic effects on intrathoracic malignacies such as lung cancer and lymph metastasis