Utility of Basophil Activation Test in a Case of Daisaikoto- and Yokukansan-induced Lung Injury.

Drug-induced lung injury is defined as a respiratory disorder. The usefulness of the basophil activation test (BAT) for drug allergy-related cases was recently reported. The patient was an 82-year-old woman who had been taking Daisaikoto and Yokukansan (herbal medicines) 3 months before developing dry cough. She was admitted to our hospital with an initial diagnosis of pneumonia with elevated serum LDH, KL-6, and IgE. Chest CT showed bilateral ground-glass opacities. Her bronchoalveolar lavage fluid showed increased eosinophils. Finally, a BAT was positive for both medications. Based on the findings, the patient was diagnosed with Daisaikoto- and Yokukansan-induced lung injury. The current case suggests that the BAT may be useful for the diagnosis of drug-induced lung injury.

Exposure to intermittent hypoxia inhibits allergic airway inflammation in a murine model of asthma.

PURPOSE: Obesity increases the severity of asthma, and patients with severe asthma are often complicated with obstructive sleep apnea syndrome (OSAS), a concomitant disease of obesity. We investigated whether intermittent hypoxia (IH), which is a physiological feature of OSAS, modifies allergic airway inflammation in a murine model of asthma. METHODS: Balb/c mice were sensitized by ovalbumin (OVA) intraperitoneally twice (days 1 and 14) and challenged with intranasal OVA three times (days 21, 22, and 23). The mice were exposed to IH either from days 1 to 24 (long exposure) or only from days 21 to 24 (short exposure). The impact of IH exposure to allergic airway inflammation was investigated using these mice models by histologic, morphometric, and molecular techniques. Additionally, the airway responsiveness to acetylcholine was also assessed. RESULTS: OVA-sensitized and OVA-challenged mice exposed to room air (RA) showed increased total cell and eosinophil numbers in the BALF. The levels of interleukin (IL)-5 and IL-13 in the BALF also increased and goblet cell metaplasia was induced. In contrast, both long and short exposure to IH inhibited the increased total cell and eosinophil numbers. The levels of IL-5 and IL-13 in the BALF also decreased on exposure to IH. Moreover, the goblet cell hyperplasia and airway hyperresponsiveness were significantly reduced in mice exposed to IH compared to those exposed to RA. CONCLUSIONS: These results suggest that IH may not deteriorate the asthmatic condition in a murine model of asthma.

Lipid Profile of Activated Macrophages and Contribution of Group V Phospholipase A2.

Macrophages activated by Interleukin (IL)-4 (M2) or LPS+ Interferon (IFN)γ (M1) perform specific functions respectively in type 2 inflammation and killing of pathogens. Group V phospholipase A2 (Pla2g5) is required for the development and functions of IL-4-activated macrophages and phagocytosis of pathogens. Pla2g5-generated bioactive lipids, including lysophospholipids (LysoPLs), fatty acids (FAs), and eicosanoids, have a role in many diseases. However, little is known about their production by differentially activated macrophages. We performed an unbiased mass-spectrometry analysis of phospholipids (PLs), LysoPLs, FAs, and eicosanoids produced by Wild Type (WT) and Pla2g5-null IL-4-activated bone marrow-derived macrophages (IL-4)BM-Macs (M2) and (LPS+IFNγ)BM-Macs (M1). Phosphatidylcholine (PC) was preferentially metabolized in (LPS+IFNγ)BM-Macs and Phosphatidylethanolamine (PE) in (IL-4)BM-Macs, with Pla2g5 contributing mostly to metabolization of selected PE molecules. While Pla2g5 produced palmitic acid (PA) in (LPS+IFNγ)BM-Macs, the absence of Pla2g5 increased myristic acid (MA) in (IL-4)BM-Macs. Among eicosanoids, Prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) were significantly reduced in (IL-4)BM-Macs and (LPS+IFNγ)BM-Macs lacking Pla2g5. Instead, the IL-4-induced increase in 20-carboxy arachidonic acid (20CooH AA) was dependent on Pla2g5, as was the production of 12-hydroxy-heptadecatrienoic acid (12-HHTrE) in (LPS+IFNγ)BM-Macs. Thus, Pla2g5 contributes to PE metabolization, PGE2 and PGD2 production independently of the type of activation, while in (IL-4)BM-Macs, Pla2g5 regulates selective lipid pathways and likely novel functions.

Acute exacerbation of idiopathic pulmonary fibrosis induced by pertussis: the first case report.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe condition with limited treatment strategies. Although respiratory infection is a major cause of AE-IPF, no reports have indicated pertussis infection as a cause. Here we report two cases of pertussis infection-induced AE-IPF. CASE PRESENTATION: Both patients presented with a chief complaint of acute respiratory distress and were previously diagnosed with idiopathic pulmonary fibrosis (IPF). Neither patient had received any pertussis vaccination since adolescence. Both patients were diagnosed with AE-IPF accompanying acute pertussis infection based on chest computed tomography and serum pertussis toxin antibody > 100 EU/mL. Both patients were treated with macrolide antibiotics and systemic corticosteroids. Both patients were able to be discharged and return home. CONCLUSIONS: The presence of pertussis infection in AE-IPF can present a diagnostic challenge, as coughing accompanying pertussis may be difficult to distinguish from IPF-associated coughing. Pertussis infection should be assayed in AE-IPF patients. Since pertussis can be prevented with vaccination and is expected to be affected by antibiotics, consideration of pertussis infection as a causative virulent factor of AE-IPF may be important for management of subjects with IPF.

PLA2G5 regulates transglutaminase activity of human IL-4-activated M2 macrophages through PGE2 generation.

Phospholipases A2 are enzymes that liberate membrane-bound lipids in a tissue and cell-specific fashion. Group V secretory phospholipase A2 is necessary for the development of M2 macrophages and their effector functions in a mouse model of the T-helper-2 allergic airway inflammation. However, the function of group V phospholipase A2 in human M2 activation and T-helper-2 inflammation is ill-defined. Transglutaminase-2, a protein cross-linking enzyme, is a newly identified marker of both human and mouse interleukin-4-activated M2 macrophages and is also found in the lungs of patients with asthma. We report that group V phospholipase A2 and transglutaminase-2 colocalized in macrophages of human nasal polyp tissue obtained from patients with T-helper-2 eosinophilic inflammation, and their coexpression positively correlated with the number of eosinophils in each tissue specimen. We demonstrate that in human monocyte-derived macrophages activated by interleukin-4, group V phospholipase A2 translocated and colocalized with transglutaminase-2 in the cytoplasm and on the membrane of macrophages. Moreover, knocking down group V phospholipase A2 with small interfering ribonucleic acid reduced macrophage transglutaminase activity, whereas mass spectrometry analysis of lipids also showed reduced prostaglandin E2 production. Finally, exogenous prostaglandin E2 restored transglutaminase activity of group V phospholipase A2-small interfering ribonucleic acid-treated macrophages. Thus, our study shows a novel function of group V phospholipase A2 in regulating the transglutaminase activity of human interleukin-4-activated M2 macrophages through prostaglandin E2 generation and suggests that group V phospholipase A2 is a functionally relevant enzyme that may have therapeutic value for the treatment of human T-helper-2 inflammatory disorders.

Expression and effects of IL-33 and ST2 in allergic bronchial asthma: IL-33 induces eotaxin production in lung fibroblasts.

BACKGROUND: Interleukin (IL)-33, a new member of the IL-1 cytokine family, has been recognized as a key cytokine that enhances T helper 2-balanced immune regulation through its receptor ST2; however, the function and relationship of the IL-33 and ST2 pathways in bronchial asthma are still unclear. We investigated the cellular origin and regulation of IL-33 and ST2 in allergic bronchial asthma in vivo and in vitro. METHODS: BALB/c mice were sensitized by intraperitoneal injections of ovalbumin (OVA) with alum. Mice were exposed to aerosolized 1% OVA for 30 min a day for 7 days. These mice were then challenged with aerosolized 1% OVA 2 days after the last day of exposure. After the OVA challenge, the mice were sacrificed and their lung tissues were obtained. Mouse lung fibroblasts were cultured and treated with IL-33 or IL-13. RESULTS: The levels of IL-33 mRNA and IL-33 protein in lung tissue increased after the OVA challenge. Most IL-33-expressing cells were CD11c+ cells and epithelial cells, and many ST2-expressing cells were stained lung fibroblasts and inflammatory cells. IL-33 induced eotaxin/CCL11 production in lung fibroblasts. IL-33 and IL-13 synergistically induced eotaxin expression. CONCLUSIONS: IL-33 may contribute to the induction and maintenance of eosinophilic inflammation in the airways by acting on lung fibroblasts. IL-33 and ST2 may play important roles in allergic bronchial asthma.

Oxaliplatin-induced lung injury with allergic reaction.

A 79-year-old man was diagnosed as stage IV colon cancer and treated with a modified FOLFOX6 (mFOLFOX6) regimen. On the 12th cycle, we observed erythema and dyspnea. Radiographs showed ground grass opacities. Blood tests showed elevated levels of eosinophils and immunoglobulin E. We diagnosed this finding as response to drug allergy and administered high-dose methylprednisolone. The treatment was successful and he was discharged. The drug lymphocyte stimulating test against oxaliplatin was positive, indicating a type I and IV allergic reaction due to oxaliplatin. Regimens including oxaliplatin must be carefully monitored and frequent blood tests and chest radiographs are needed.