Sang Pyo Lee

Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling

The ingestion of apoptotic cells (ACs; termed “efferocytosis”) by phagocytes has been shown to trigger the release of molecules such as transforming growth factor β, interleukin-10 (IL-10), nitric oxide, and prostaglandin E2 (PGE2). Although the antiinflammatory actions of these mediators may contribute to the restoration of homeostasis after tissue injury, their potential impact on antibacterial defense is unknown. The lung is highly susceptible to diverse forms of injury, and secondary bacterial infections after injury are of enormous clinical importance. We show that ACs suppress in vitro phagocytosis and bacterial killing by alveolar macrophages and that this is mediated by a cyclooxygenase–PGE2–E prostanoid receptor 2 (EP2)–adenylyl cyclase–cyclic AMP pathway. Moreover, intrapulmonary administration of ACs demonstrated that PGE2 generated during efferocytosis and acting via EP2 accounts for subsequent impairment of lung recruitment of polymorphonuclear leukocytes and clearance of Streptococcus pneumoniae, as well as enhanced generation of IL-10 in vivo. These results suggest that in addition to their beneficial homeostatic influence, antiinflammatory programs activated by efferocytosis in the lung have the undesirable potential to dampen innate antimicrobial responses. They also identify an opportunity to reduce the incidence and severity of pneumonia in the setting of lung injury by pharmacologically targeting synthesis of PGE2 or ligation of EP2.

Effects of ambient particulate matter on peak expiratory flow rates and respiratory symptoms of asthmatics during Asian dust periods in Korea

Objective:  Dust generating events frequently produce ambient dust particles that are less than 10 µm in diameter, and these have been linked to adverse effects in the general population. However, the evidence linking these particles to adverse effects on the airways of asthmatic individuals is limited. The objective of this study was to investigate the possible adverse effects of Asian dust events on the respiratory functions and symptoms of subjects with bronchial asthma.

Effect of multispecies probiotics on irritable bowel syndrome: A randomized, double-blind, placebo-controlled trial

The efficacy of treatment with multispecies probiotics on irritable bowel syndrome (IBS) symptoms and the alterations of gut microbiota in patients who have taken probiotics were investigated.

PTEN Directly Activates the Actin Depolymerization Factor Cofilin-1 During PGE2-Mediated Inhibition of Phagocytosis of Fungi

By promoting actin depolymerization, the protein phosphatase activity of PTEN impairs macrophage phagocytosis of a fungal pathogen. Preventing Phagocytosis The fungus Candida albicans is normally a commensal microbe found on mucosal surfaces, including those in the lung. However, C. albicans can cause systemic infections that are a leading cause of morbidity and mortality in immunocompromised individuals. A key innate immune response to C. albicans is its ingestion (phagocytosis) by macrophages, a process that requires polymerization of the actin cytoskeleton. Another component of the macrophage response to fungus is the production of prostaglandin E2 (PGE2), a lipid mediator whose synthesis is initiated by cyclooxygenase (COX) enzymes. Serezani et al. found that infection of alveolar macrophages with C. albicans triggered the production of PGE2, which prevented polymerization of the actin cytoskeleton and inhibited phagocytosis of C. albicans by alveolar macrophages. The authors defined the signaling pathway involved. These results suggest that COX inhibitors, such as aspirin, which are in widespread clinical use, may stimulate innate immune responses. In addition, immunosuppression is associated with increased production of PGE2, which may help to explain how antifungal responses are attenuated in immunocompromised individuals. Macrophage ingestion of the yeast Candida albicans requires its recognition by multiple receptors and the activation of diverse signaling programs. Synthesis of the lipid mediator prostaglandin E2 (PGE2) and generation of cyclic adenosine monophosphate (cAMP) also accompany this process. Here, we characterized the mechanisms underlying PGE2-mediated inhibition of phagocytosis and filamentous actin (F-actin) polymerization in response to ingestion of C. albicans by alveolar macrophages. PGE2 suppressed phagocytosis and F-actin formation through the PGE2 receptors EP2 and EP4, cAMP, and activation of types I and II protein kinase A. Dephosphorylation and activation of the actin depolymerizing factor cofilin-1 were necessary for these inhibitory effects of PGE2. PGE2-dependent activation of cofilin-1 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated. Because enhanced production of PGE2 accompanies many immunosuppressed states, the PTEN-dependent pathway described here may contribute to impaired antifungal defenses.

Crosstalk between Prostaglandin E2 and Leukotriene B4 Regulates Phagocytosis in Alveolar Macrophages via Combinatorial Effects on Cyclic AMP

Eicosanoid lipid mediators, including prostaglandin E2 (PGE2) and leukotrienes (LTs) B4 and D4, are produced in abundance in the infected lung. We have previously demonstrated that individually, PGE2 suppresses while both classes of LTs augment alveolar macrophage (AM) innate immune functions. In this study, we sought to more appropriately model the milieu at a site of infection by studying the in vitro effects of these lipid mediators on FcγR-mediated phagocytosis when they are present in combination. Consistent with their individual actions, both LTB4 and LTD4 opposed the suppressive effect of PGE2 on phagocytosis, but only LTB4 did so by mitigating the stimulatory effect of PGE2 on intracellular cAMP production. Unexpectedly, we observed that IgG-opsonized targets themselves elicited a dose-dependent reduction in intracellular cAMP in AMs, but this was not observed in peritoneal macrophages or elicited peritoneal neutrophils; this effect in AMs was completely abolished by treatment with the LT synthesis inhibitor AA861, the BLT receptor 1 antagonist CP 105,696, and the Gαi inhibitor pertussis toxin. Of two downstream cAMP effectors, protein kinase A and exchange protein activated by cAMP, the ability of PGE2 to activate the latter but not the former was abrogated by both LTs B4 and D4. Taken together, our results indicate that both classes of LTs oppose the immune suppressive actions of PGE2, with the stimulatory actions of LTB4 reflecting combinatorial modulation of intracellular cAMP and those of LTD4 being cAMP independent.

Mast cell number, substance P and vasoactive intestinal peptide in irritable bowel syndrome with diarrhea

Abstract Background. Recent studies have shown that mast cells play an important role in irritable bowel syndrome (IBS). We investigated the relationship between mast cells and the gut hormones substance P and vasoactive intestinal peptide (VIP) in irritable bowel syndrome with diarrhea (IBS-D). Methods. Colonoscopic biopsies were performed on the rectal mucosa of 43 subjects (IBS-D patients: 22, healthy volunteers: 21) diagnosed according to the Rome III criteria. Mast cells, and substance P & VIP were evaluated by quantitative immunohistology and image analysis. Mast cells were counted as tryptase-positive cells in the lamina propria, and substance P and VIP levels were expressed as percentages of total areas of staining. Results. Mast cell counts were higher in IBS-D patients than healthy volunteers (9.6 ± 3.3 vs. 5.7 ± 2.5/high power field (HPF), p < 0.01). Substance P was also elevated (0.11 ± 0.08% vs. 0.03 ± 0.02 %, p < 0.01) while VIP was only high in women with IBS-D. Mast cell counts were positively correlated with levels of substance P & VIP in women but not men (women: r = 0.625, p < 0.01 for substance P and r = 0.651, p < 0.01 for VIP). However, mast cell counts were not correlated with IBS symptoms including abdominal pain. Conclusion. Mast cells are activated leading to the raised levels of substance P & VIP in IBS-D patients. However, the correlation between mast cells and levels of substance P & VIP differs according to gender.

Randomized phase II trial of two different schedules of docetaxel plus cisplatin as first‐line therapy in advanced nonsmall cell lung cancer

There is increasing interest in the use of a weekly administration of docetaxel as a way of reducing its hematologic toxicity. The purpose of the current randomized study was to evaluate the toxicity and efficacy of docetaxel plus cisplatin combination on 2 schedules in patients with previously untreated, advanced nonsmall‐cell lung cancer (NSCLC).

Pemetrexed versus gefitinib versus erlotinib in previously treated patients with non-small cell lung cancer.

Background/Aims The efficacy and safety of pemetrexed, gefitinib, and erlotinib administration in previously treated patients with non-small cell lung cancer (NSCLC) were compared. Methods The study patients met the following criteria: histologically confirmed, previously treated advanced (stage IIIB or IV) or recurrent NSCLC; a measurable lesion; ≥ 18 years of age; Eastern Cooperative Oncology Group Performance status 0 to 2; and no prior exposure to the three study drugs. Patients received 500 mg/m2 of pemetrexed intravenously every 3 weeks with vitamin supplementation, gefitinib (250 mg/day per os), or erlotinib (150 mg/day per os). Results Of 57 patients (pemetrexed, 20; gefitinib, 20; and erlotinib, 17), 55 were evaluated for a response. The numbers of males, smokers, and squamous histology were increased in the pemetrexed group compared to the other groups. The objective response rates were 5.3%, 25.0%, and 12.5% (p = 0.22), and the disease control rates (DCR) were 5.3%, 40.0%, and 50.0%, respectively (p < 0.01). The median progression-free survival (PFS) was 1.7, 3.5, and 4.4 months (p < 0.01) and the median overall survival (OS) was 5.6, 21.8, and 21.5 months (p = 0.04), respectively. In subgroup analyses, patients with non-squamous histology, males, and a smoking history had a higher DCR and longer PFS with gefitinib and erlotinib than with pemetrexed. All three chemotherapeutic agents had manageable toxicities. Conclusions Both oral epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) had comparable efficacy and safety. The superior PFS and OS of EGFR TKIs with more favorable baseline clinical characteristics than those of pemetrexed suggest the impact of baseline clinicopathological factors.

Toxocariasis Masquerading as Liver and Lung Metastatic Nodules in Patents with Gastrointestinal Cancer: Clinicopathologic Study of Five Cases

BackgroundThere are sporadic reports in the literature in which radiologic liver and lung lesions found incidentally during follow-up metastatic surveillance were shown to be caused by toxocariasis.AimsThe objective of the work discussed in this report was to identify common clinical and histopathological features of toxocariasis resembling metastatic nodules in five patients with gastrointestinal cancer.MethodsWe retrospectively analyzed clinical features of five gastrointestinal cancer patients with liver or lung nodules mimicking metastasis. Serologic tests for parasitic infestations and pathologic examinations were performed.ResultsAll five patients were males and three patients had gastric cancer and two had colorectal cancer. All the cases of toxocariasis were confirmed serologically. On follow-up imaging, the lesions improved or resolved, suggestive of the phenomenon of visceral larva migrans. In two patients, liver biopsy was performed and showed eosinophilic abscess.ConclusionSerologic tests and liver or lung biopsy should be performed aggressively to exclude toxocariasis when patients with underlying gastrointestinal cancer present with hepatic or pulmonary nodules associated with eosinophilia, particularly if the patients have a clinical history of raw animal liver ingestion. Curative surgical intervention should not be excluded just because of multiple nodules in the liver or the lungs.

The phosphodiesterase 4 inhibitor rolipram protects against cigarette smoke extract-induced apoptosis in human lung fibroblasts

Cigarette smoke, a major causative agent of chronic obstructive pulmonary disease (COPD), induces lung cell death by incompletely understood mechanisms. The induction of apoptosis in lung structural cells by cigarette smoke may contribute to the pathogenesis of emphysema. Phosphodiesterase-4 (PDE4) inhibitors are anti-inflammatory agents used in COPD therapy that can prevent cigarette smoke-induced emphysema in mice. We investigated the effect of rolipram, a first generation PDE4 inhibitor, on the regulation of cigarette smoke-induced apoptosis. Human lung fibroblast (MRC-5) cells were exposed to cigarette smoke extract (CSE). Cell viability and apoptosis were determined by MTT assay and Annexin-V staining, respectively. Caspase activation was determined by Western immunoblot analysis. Rolipram protected against cell death and increased viability in MRC-5 fibroblasts after CSE exposure. Furthermore, rolipram protected against apoptosis, decreased caspase-3 and -8 cleavage in MRC-5 cells exposed to CSE. Pre-treatment with rolipram enhanced Akt phosphorylation and associated cytoprotection in CSE-treated cells, which could be reversed by the PI3K inhibitor LY294002 partly. In conclusion, rolipram protects against apoptosis of MRC-5 cells through inhibition of caspase-3 and caspase-8. Rolipram may represent an effective therapeutic agent to reduce cigarette smoke-induced apoptosis of lung fibroblasts.