CCN1 Secretion Induced by Cigarette Smoking Extracts Augments IL-8 Release from Bronchial Epithelial Cells

Inflammation involves in many cigarette smoke (CS) related diseases including the chronic obstructive pulmonary disease (COPD). Lung epithelial cell released IL-8 plays a crucial role in CS induced lung inflammation. CS and cigarette smoke extracts (CSE) both induce IL-8 secretion and subsequently, IL-8 recruits inflammatory cells into the lung parenchyma. However, the molecular and cellular mechanisms by which CSE triggers IL-8 release remain not completely understood. In this study, we identified a novel extracellular matrix (ECM) molecule, CCN1, which mediated CSE induced IL-8 secretion by lung epithelial cells. We first found that CS and CSE up-regulated CCN1 expression and secretion in lung epithelial cells in vivo and in vitro. CSE up-regulated CCN1 via induction of reactive oxygen spices (ROS) and endoplasmic reticulum (ER) stress. p38 MAPK and JNK activation were also found to mediate the signal pathways in CSE induced CCN1. CCN1 was secreted into ECM via Golgi and membrane channel receptor aquaporin4. After CSE exposure, elevated ECM CCN1 functioned via an autocrine or paracrine manner. Importantly, CCN1 activated Wnt pathway receptor LRP6, subsequently stimulated Wnt pathway component Dvl2 and triggered beta-catenin translocation from cell membrane to cytosol and nucleus. Treatment of Wnt pathway inhibitor suppressed CCN1 induced IL-8 secretion from lung epithelial cells. Taken together, CSE increased CCN1 expression and secretion in lung epithelial cells via induction of ROS and ER stress. Increased ECM CCN1 resulted in augmented IL-8 release through the activation of Wnt pathway

Cross-talk between apoptosis and autophagy in lung epithelial cell death

Abstract: As an essential organ for gas exchange, the lungs are constantly exposed to the external environment and are simulated by toxicants and pathogens. The integrity of lung epithelium and epithelial cells is crucial for fulfilling the physiological functions of the lung. The homeostasis of lung epithelial cells is maintained by a complex network by which survival and death are tightly regulated. Upon noxious stimulation, lung epithelium attempts to maintain its normal structure and function. Savage of injured cells and clearance of unsalvageable dying cells or unwanted proliferated cells constantly occur in the lung epithelium. Apoptosis, or programmed cell death, functions as a primary mechanism to discard unsalvageable cells or unwanted overgrowth. Autophagy, on the other hand, initially attempts to save and repair the injured cells. However, when the noxious stimulation is too strong and cell survival becomes unfeasible, autophagy behaves oppositely and cooperates with apoptosis, subsequently accelerates cell death. The imbalance between autophagy and apoptosis potentially leads to tumorigenesis or devastating cell death/lung injury. Therefore, the cross-talk between apoptosis and autophagy in lung epithelial cells is critical in determining the fate of epithelial cells and its balance of death/survival in response to environmental stimuli. In this review, we will focus on the current understandings of the communications between apoptosis and autophagy in lung epithelial cells. We will review multiple key regulators and their underlying mechanisms involved in the cross-talk between apoptosis and autophagy. The autophagic factors, such as the Beclin-1, ATG5, Fap-1, p62 and concentration-dependent LC3B, all closely interact with multiple apoptosis pathways. Understanding these regulations of apoptosis / autophagy cross-talk potentially provides novel targets for developing diagnostic and therapeutic strategies for many lung diseases, including lung injuries and malignancies

Flotillin-2 Modulates Fas Signaling Mediated Apoptosis after Hyperoxia in Lung Epithelial Cells

Lipid rafts are subdomains of the cell membrane with distinct protein composition and high concentrations of cholesterol and glycosphingolipids. Raft proteins are thought to mediate diverse cellular processes including signal transduction. However, its cellular mechanisms remain unclear. Caveolin-1 (cav-1, marker protein of caveolae) has been thought as a switchboard between extracellular matrix (ECM) stimuli and intracellular signals. Flotillin-2/reggie-1(Flot-2) is another ubiquitously expressed raft protein which defines non-caveolar raft microdomains (planar raft). Its cellular function is largely uncharacterized. Our novel studies demonstrated that Flot-2, in conjunction with cav-1, played important functions on controlling cell death via regulating Fas pathways. Using Beas2B epithelial cells, we found that in contrast to cav-1, Flot-2 conferred cytoprotection via preventing Fas mediated death-inducing signaling complex (DISC) formation, subsequently suppressed caspase-8 mediated extrinsic apoptosis. Moreover, Flot-2 reduced the mitochondria mediated intrinsic apoptosis by regulating the Bcl-2 family and suppressing cytochrome C release from mitochondria to cytosol. Flot-2 further modulated the common apoptosis pathway and inhibited caspase-3 activation via up-regulating the members in the inhibitor of apoptosis (IAP) family. Last, Flot-2 interacted with cav-1 and limited its expression. Taken together, we found that Flot-2 protected cells from Fas induced apoptosis and counterbalanced the pro-apoptotic effects of cav-1. Thus, Flot-2 played crucial functions in cellular homeostasis and cell survival, suggesting a differential role of individual raft proteins

Matrix protein CCN1 induced by bacterial DNA and CpG ODN limits lung inflammation and contributes to innate immune homeostasis

Summary To defend against pulmonary infections, lung epithelial cells are equipped with complex innate immunity closely linked to inflammation. Dysregulated innate immunity / inflammation leads to self-perpetuating lung injury. The CpG motif in bacterial DNA is one of the factors involved in bacterial infection-associated inflammation. Bacterial DNA and synthetic CpG oligonucleotide (ODN) induced CCN1 secretion from lung epithelial cells, functioning as a potential “braking” signal to prevent uncontrolled inflammatory responses. CpG ODN-induced ER stress resulted in Src-Y527 phosphorylation (pY527) and Src/CCN1 vWF domain dissociation. Src-Y527 activated caveolin-1 (cav-1) phosphorylation at Y14 and then modulated CCN1 secretion via pCav-1 interaction with CCN1 IGFbp domain. Functionally, secreted CCN1 promoted anti-inflammatory cytokine IL-10 release from epithelial cells via integrin αVβ6 PKC, and this subsequently suppressed TNF-α, MIP-2 secretion and neutrophil infiltration in the lungs. Collectively, bacterial DNA/CpG ODN-stimulated CCN1 secretion via BiP/GRP78-Src(Y527)-JNK-Cav-1(Y14) pathway and CpG-induced CCN1 conferred anti-inflammatory roles. Our studies suggested a novel paradigm by which the lung epithelium maintains innate immune homeostasis after bacterial infection

Safe and cost-effective method for application of liquid ethyl formate (FumateTM) as a methyl bromide alternative for perishable commodities: Poster

The cylinderized liquid ethyl formate (EF) formulated with CO2 is one of the great potential fumigants to replace methyl bromide (MeBr) for fresh fruit. However, it is too expensive to adapt commercial practices, and also involves work place safety issue including handling of heavy cylinders as well as restrict emission of CO2, particularly for use in large scale commercial fumigationw. Therefore, it is urgently needed to develop environmental friendly, safe for workers and cost-effective alternative method for application of liquid ethyl formate as a MeBr alternative for perishable commodities. Recently, the environmentally friendly, cost-effective and practically safe use of liquid EF (FumateTM, registered name) with nitrogen gas has been developed and commercialized in Republic of Korea and Australia. The new technology for application of liquid EF is 100 times safer than MeBr in terms of threshold values (EF, TLV = 100 ppm). Ethyl formate is known as food additive and naturally occurred substances as well as a non-ozone depletion chemical. In this report, we demonstrate the liquid EF application technology that offers a clean environment (no ozone depletions and CO2 emissions), safe to fumigators and related workers and practically cost-effective technology to fumigation industry.The cylinderized liquid ethyl formate (EF) formulated with CO2 is one of the great potential fumigants to replace methyl bromide (MeBr) for fresh fruit. However, it is too expensive to adapt commercial practices, and also involves work place safety issue including handling of heavy cylinders as well as restrict emission of CO2, particularly for use in large scale commercial fumigationw. Therefore, it is urgently needed to develop environmental friendly, safe for workers and cost-effective alternative method for application of liquid ethyl formate as a MeBr alternative for perishable commodities. Recently, the environmentally friendly, cost-effective and practically safe use of liquid EF (FumateTM, registered name) with nitrogen gas has been developed and commercialized in Republic of Korea and Australia. The new technology for application of liquid EF is 100 times safer than MeBr in terms of threshold values (EF, TLV = 100 ppm). Ethyl formate is known as food additive and naturally occurred substances as well as a non-ozone depletion chemical. In this report, we demonstrate the liquid EF application technology that offers a clean environment (no ozone depletions and CO2 emissions), safe to fumigators and related workers and practically cost-effective technology to fumigation industry

Safe and high efficient method for application of liquid ethyl formate (FumateTM) to replace methyl bromide for treatment of imported nursery plants: Poster

There have been significantly increased reports of finding invasive quarantine pests with increasing import plants into Korea. Moreover, the efficacy and work safety issues have been reported regarding use of methyl bromide (MeBr) for fumigation of imported nursery plants. For replacement of MeBr use on imported plants, a new technology of using liquid ethyl formate has been registered in South Korea as FumateTM. The technology involved to mix ethyl format with nitrogen gas to form non-flamable ethyl format formulation. It has been evaluated on various imported plants. The FumateTM is recently developed and commercialized in Republic of Korea and Australia for quarantine treatments on fresh fruits, grains etc. Fumigation with FumateTM offers environmental-friendly and practically safe use of liquid ethyl formate. We have extended the use of liquid EF application technology to quarantine treatment of imported nursery plants.There have been significantly increased reports of finding invasive quarantine pests with increasing import plants into Korea. Moreover, the efficacy and work safety issues have been reported regarding use of methyl bromide (MeBr) for fumigation of imported nursery plants. For replacement of MeBr use on imported plants, a new technology of using liquid ethyl formate has been registered in South Korea as FumateTM. The technology involved to mix ethyl format with nitrogen gas to form non-flamable ethyl format formulation. It has been evaluated on various imported plants. The FumateTM is recently developed and commercialized in Republic of Korea and Australia for quarantine treatments on fresh fruits, grains etc. Fumigation with FumateTM offers environmental-friendly and practically safe use of liquid ethyl formate. We have extended the use of liquid EF application technology to quarantine treatment of imported nursery plants

Experiments and failure analysis of SHCC and reinforced concrete composite slabs

For all types of concrete structures, controlling of cracking, as well as the enhancement of serviceability and ultimate flexural capacity are important issues for deck slabs. This study presents an experimental campaign and accompanying nonlinear analysis of a series of Strain Hardening Cementitious Composite (SHCC) and reinforced concrete slab systems, simply-supported and subjected to four-point loading. In order to improve flexural performance both at the service and ultimate limit states, an SHCC layer with thickness of 150–400 mm was placed on the soffit of the composite slab; the SHCC was manufactured using two different processes, namely cast-in-situ SHCCs and extruded precast SHCC panel. Nonlinear analysis of SHCC and reinforced concrete slabs was also carried out to predict moment and curvature as well as deflections of the slab systems. The developed slab systems were found to have enhanced performance with regard to both at serviceability and flexural capacity, compared to the conventional reinforced concrete slab

Primary Idiopathic Chylopericardium Associated with Cervicomediastinal Cystic Hygroma

Chylopericardium is a rare clinical entity in which chylous fluid accumulates in the pericardial cavity. We report a case of primary idiopathic chylopericardium associated with multiple, small cervicomediastinal cystic hygromas occurring in an asymptomatic 43-year-old woman with no history of trauma, thoracic surgery, malignancy, infection or tuberculosis. Echocardiography showed a large amount of pericardial effusions and pericardial fluid analysis revealed inappropriately elevated triglyceride. We did not demonstrate communication between the thoracic duct and the pericardial sac by lymphangiography and chest computed tomography. She successfully responded to 30 days of continuous pericardial drainage and 15 days of a medium-chain triglyceride diet after 30 days of total parenteral nutrition. Follow-up echocardiography 6 months after treatment commencement showed a minimal reaccumulation of pericardial fluid without symptom. We conclude that if a patient is asymptomatic and can well tolerate daily life, surgery including pericardiectomy or ligation of the thoracic duct is not necessarily required

Protection of nigral dopaminergic neurons by AAV1 transduction with Rheb(S16H) against neurotoxic inflammation in vivo

We recently reported that adeno-associated virus serotype 1 (AAV1) transduction of murine nigral dopaminergic (DA) neurons with constitutively active ras homolog enriched in brain with a mutation of serine to histidine at position 16 [Rheb(S16H)] induced the production of neurotrophic factors, resulting in neuroprotective effects on the nigrostriatal DA system in animal models of Parkinson's disease (PD). To further investigate whether AAV1-Rheb(S16H) transduction has neuroprotective potential against neurotoxic inflammation, which is known to be a potential event related to PD pathogenesis, we examined the effects of Rheb(S16H) expression in nigral DA neurons under a neurotoxic inflammatory environment induced by the endogenous microglial activator prothrombin kringle-2 (pKr-2). Our observations showed that Rheb(S16H) transduction played a role in the neuroprotection of the nigrostriatal DA system against pKr-2-induced neurotoxic inflammation, even though there were similar levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta), in the AAV1-Rheb(S16H)-treated substantia nigra (SN) compared to the SN treated with pKr-2 alone; the neuroprotective effects may be mediated by the activation of neurotrophic signaling pathways following Rheb(S16H) transduction of nigral DA neurons. We conclude that AAV1-Rheb(S16H) transduction of neuronal populations to activate the production of neurotrophic factors and intracellular neurotrophic signaling pathways may offer promise for protecting adult neurons from extracellular neurotoxic inflammation.1