Hsi-Min Hsiao

University of Rochester, Rochester, New York, United States

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Publications (11)23.35 Total impact

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    ABSTRACT: Chronic obstructive pulmonary disease is characterized, in part, by chronic inflammation that persists even after smoking cessation, suggesting that a failure to resolve inflammation plays an important role in the pathogenesis of the disease. It is widely recognized that the resolution of inflammation is an active process, governed by specialized proresolving lipid mediators, including lipoxins, resolvins, maresins, and protectins. Here, we report that proresolving signaling and metabolic pathways are disrupted in lung tissue from patients with chronic obstructive pulmonary disease, suggesting that supplementation with proresolving lipid mediators might reduce the development of emphysema by controlling chronic inflammation. Groups of mice were exposed long-term to cigarette smoke and treated with the proresolving mediator resolvin D1. Resolvin D1 was associated with a reduced development of cigarette smoke-induced emphysema and airspace enlargement, with concurrent reductions in inflammation, oxidative stress, and cell death. Interestingly, resolvin D1 did not promote the differentiation of M2 macrophages and did not promote tissue fibrosis. Taken together, our results suggest that cigarette smoking disrupts endogenous proresolving pathways and that supplementation with specialized proresolving lipid mediators is an important therapeutic strategy in chronic lung disease, especially if endogenous specialized proresolving lipid mediator signaling is impaired.
    No preview · Article · Oct 2015 · American Journal Of Pathology
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    ABSTRACT: The respiratory epithelium consists of lung sentinel cells, which are the first to contact inhaled inflammatory insults, including air pollutants, smoke, and microorganisms. To avoid damaging exuberant or chronic inflammation, the inflammatory process must be tightly controlled and terminated once the insult is mitigated. Inflammation resolution is now known to be an active process involving a new genus of lipid mediators, called "specialized proresolving lipid mediators," that includes resolvin D1 (RvD1). We and others have reported that RvD1 counteracts proinflammatory signaling and promotes resolution. A knowledge gap is that the specific cellular targets and mechanisms of action for RvD1 remain largely unknown. In this article, we identified the mechanism whereby RvD1 disrupts inflammatory mediator production induced by the viral mimic polyinosinic-polycytidylic acid [poly(I:C)] in primary human lung epithelial cells. RvD1 strongly suppressed the viral mimic poly(I:C)-induced IL-6 and IL-8 production and proinflammatory signaling involving MAPKs and NF-κB. Most importantly, we found that RvD1 inhibited the phosphorylation of TAK1 (TGF-β-activated kinase 1), a key upstream regulatory kinase common to both the MAPK and NF-κB pathways, by inhibiting the formation of a poly(I:C)-induced signaling complex composed of TAK1, TAB1 (TAK1 binding protein), and TRAF6 (TNF receptor-associated factor 6). We confirmed that ALX/FPR2 and GPR32, two RvD1 receptors, were expressed on human small airway epithelial cells. Furthermore, blocking these receptors abrogated the inhibitory action of RvD1. In this article, we present the idea that RvD1 has the potential to be used as an anti-inflammatory and proresolving agent, possibly in the context of exuberant host responses to damaging respirable agents such as viruses.
    No preview · Article · Oct 2014 · The Journal of Immunology
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    ABSTRACT: Pulmonary Fibrosis (PF) is a devastating progressive disease in which normal lung structure and function is compromised by scarring. Lung fibrosis can be caused by thoracic radiation, injury from chemotherapy and systemic diseases such as rheumatoid arthritis that involve inflammatory responses. CDDO-Me (Methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, Bardoxolone methyl) is a novel triterpenoid with anti-fibrotic and anti-inflammatory properties as shown by our in vitro studies. Based on this evidence, we hypothesized that CDDO-Me would reduce lung inflammation, fibrosis and lung function impairment in a bleomycin model of lung injury and fibrosis. To test this hypothesis, mice received bleomycin via oropharyngeal aspiration (OA) on day zero and CDDO-Me during the inflammatory phase from days -1 to 9 every other day. Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested on day 7 to evaluate inflammation, while fibrosis and lung function were evaluated on day 21. On day 7, CDDO-Me reduced total BALF protein by 50%, alveolar macrophage infiltration by 40%, neutrophil infiltration by 90% (p≤0.01), inhibited production of the inflammatory cytokines KC and IL-6 by over 90% (p≤0.001), and excess production of the pro-fibrotic cytokine TGFβ by 50%. CDDO-Me also inhibited α-smooth muscle actin and fibronectin mRNA by 50% (p≤0.05). On day 21, CDDO-Me treatment reduced histological fibrosis, collagen deposition and αSMA production. Lung function was significantly improved at day 21 by treatment with CDDO-Me, as demonstrated by respiratory rate and dynamic compliance. These new findings reveal that CDDO-Me exhibits potent anti-fibrotic and anti-inflammatory properties in vivo. CDDO-Me is a potential new class of drugs to arrest inflammation and ameliorate fibrosis in patients who are predisposed to lung injury and fibrosis incited by cancer treatments (e.g. chemotherapy and radiation) and by systemic autoimmune diseases.
    No preview · Article · May 2013 · PLoS ONE
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    ABSTRACT: Rationale: Cigarette smoke induced-chronic obstructive pulmonary disease (COPD, emphysema and chronic bronchitis) is an increasing health burden worldwide. Current therapies only treat the symptoms without having any effect on altering the course of the disease; therefore, new therapies are desperately needed. Resolution of inflammation was once believed to be passive. However, a new paradigm shows that resolution is a biosynthetically active process involving endogenous pro-resolving lipid mediators including Resolvin D1 (RvD1). RvD1 is produced in the body from dietary ω-3 polyunsaturated fatty acids and has ability to control and limit inflammatory response without being immunosuppressive. Previously, we demonstrated that RvD1 prevents acute cigarette smoke-induced lung inflammation and promotes resolution in a preclinical mouse model. Here, we hypothesized that RvD1 will also attenuate cigarette smoke-induced chronic lung disease and airspace destruction. Methods: Female A/J mice were exposed to cigarette smoke 5 hours/day, 5 days/week for 12 weeks. RvD1 (500ng) was given by inhalation twice a week. Following euthanasia, lungs were inflated with agarose under 25cm pressure and processed for morphometry. Accumulation of inflammatory cells was visualized by immunohistochemistry and gene expression was assessed by quantitative PCR. Apoptosis was assessed by TUNEL staining. To better understand the underlying mechanisms, primary human lung fibroblasts and epithelial cells were exposed to cigarette smoke extract and treated with RvD1, and apoptosis was assessed by flow cytometry and Western blotting. Results: RvD1 inhibited development of airspace enlargement in mice chronically exposed to cigarette smoke, compared with vehicle alone. RvD1-treated mice had reduced numbers of inflammatory cells. IL-6 mRNA in RvD1-treated lung was reduced by 65% and KC by 30%. RvD1 increased mRNA levels of the anti-inflammatory mediator IL-10 by 2-fold. RvD1 also reduced the number of TUNEL-positive cells in mouse lung sections. In vitro, RvD1 dampened cigarette smoke extract-induced mitochondrial dysfunction and subsequent PARP cleavage. Conclusion: RvD1 attenuated cigarette smoke-induced airspace enlargement with reductions in pro-inflammatory mediators and lung cell apoptosis, two mechanisms believed to be important in the pathogenesis of emphysema. We suggest that RvD1 has potential as a novel therapeutic agent to treat emphysema. Because resolvins are anti-inflammatory without being immunosuppressive, they may have additional advantages when treating COPD patients who are subject to viral and bacterial exacerbations. This work was supported by National Institutes of Health Grants R01HL088325, RO1HL088325-02S1, T32HL66988, T32ES07026, 8UL1TR000042 and P30ES01247.
    No preview · Conference Paper · May 2013
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    ABSTRACT: Rationale: Cigarette smoke is a profound pro-inflammatory stimulus and is a significant cause of multiple diseases related to chronic inflammation such as cancer and COPD. Resolution of inflammation is a bioactive process, mediated by specialized lipid mediators including resolvin D1 (RvD1). RvD1 is synthesized from dietary enriched ω-3 fatty acids and has the ability to control and limit the inflammatory response without being immunosuppressive. Previously we demonstrated that RvD1 attenuates acute cigarette smoke-induced lung inflammation and promotes the resolution of inflammation in a mouse model. Moreover, RvD1 reduces pro-inflammatory signaling in lung fibroblasts, epithelial cells and macrophages treated with cigarette smoke extract (CSE). However, how RvD1 functions is not known. Here we hypothesize that RvD1 attenuates inflammation by modulating the ERK and NF-kB inflammatory signaling pathways. We also test whether the RvD1 receptors, ALX and GPR32, are required for this unique regulatory axis. Methods: Primary human lung fibroblasts and small airway epithelial cells (SAEC) were pretreated with RvD1 (1-1000 nM) for 30 minutes prior to the addition of CSE (1%) or IL-1β (1 ng/ml), and harvested at various time points. Cell lysates were collected and analyzed by Western blotting to determined levels of p-ERK, Iκα and p-Iκα. NF-κB activity was monitored by a luciferase reporter assay. GPR32 knock down was achieved using siRNA with a lentiviral delivery system and ALX signaling was inhibited by its specific antagonist Boc-2 (3 µM). Cells were then treated with RvD1 and CSE and analyzed as above. Results: In both primary human lung fibroblasts and epithelial cells, IL-1β and CSE induced production of IL-6, IL-8 and PGE2 that was significantly inhibited RvD1. IL-1β and CSE activated ERK at 15-30 minutes and NF-κB at 60 minutes and this activation was attenuated by RvD1. The inhibition of GPR32 or ALX abolished RvD1’s anti-inflammatory ability to inhibit the activation of ERK, NF-κB and subsequent production of pro-inflammatory mediators. Conclusion: RvD1 attenuates acute inflammatory signaling by regulating ERK and NF-κB activation via a receptor-dependent mechanism. Our study will not only help us to better understand the function of RvD1 in the lung but also will aid in the development of new therapeutic options for inflammatory lung disease. This work was supported by National Institutes of Health Grants R01HL088325, RO1HL088325-02S1, T32HL66988, T32ES07026, 8UL1TR000042 and P30ES01247.
    No preview · Conference Paper · May 2013
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    ABSTRACT: Background. Cigarette smoke is a profound proinflammatory stimulus, which causes acute lung inflammation and chronic lung disease including chronic obstructive pulmonary disease (COPD, emphysema and chronic bronchitis), via a variety of mechanisms including oxidative stress. Cigarette smoke contains high levels of free radicals, while inflammatory cells including macrophages and neutrophils express enzymes including NADPH oxidase, nitric oxide synthase and myeloperoxidase that generate reactive oxygen species in situ and contribute to inflammation and tissue damage. Neu-164 and Neu-107 are small molecule inhibitors of myeloperoxidase, as well as potent antioxidants. We hypothesized that Neu-164 and Neu-107 would inhibit acute cigarette smoke-induced inflammation. Methods. Adult C57BL/6J mice were exposed to mainstream cigarette smoke for 3 days to induce acute inflammation, and were treated daily by inhalation with Neu-164, Neu-107, or dexamethasone as a control. Inflammatory cells and cytokines were assessed by bronchoalveolar lavage and histology. mRNA levels of endogenous antioxidant genes HO-1 and GCLm were determined by qPCR. Results. Cigarette smoke exposure induced acute lung inflammation with accumulation of neutrophils and upregulation of proinflammatory cytokines including IL-6, MIP-2 and KC. Both Neu-164 and Neu-107 significantly reduced the accumulation of inflammatory cells and the expression of inflammatory cytokines as effectively as dexamethasone. Upregulation of endogenous antioxidant genes was dampened. Conclusions. Neu-164 and Neu-107 inhibit acute cigarette smoke-induced inflammation by scavenging reactive oxygen species in cigarette smoke and by inhibiting further oxidative stress caused by inflammatory cells. These compounds may have promise in preventing or treating lung disease associated with chronic smoke exposure including COPD.
    Full-text · Article · May 2013 · AJP Lung Cellular and Molecular Physiology
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    ABSTRACT: Background. Cigarette smoke is a profound proinflammatory stimulus, which causes acute lung inflammation and chronic lung disease including chronic obstructive pulmonary disease (COPD, emphysema and chronic bronchitis), via a variety of mechanisms including oxidative stress. Cigarette smoke contains high levels of free radicals, while inflammatory cells including macrophages and neutrophils express enzymes including NADPH oxidase, nitric oxide synthase and myeloperoxidase that generate reactive oxygen species in situ and contribute to inflammation and tissue damage. Neu-164 and Neu-107 are small molecule inhibitors of myeloperoxidase, as well as potent antioxidants. We hypothesized that Neu-164 and Neu-107 would inhibit acute cigarette smoke-induced inflammation. Methods. Adult C57BL/6J mice were exposed to mainstream cigarette smoke for 3 days to induce acute inflammation, and were treated daily by inhalation with Neu-164, Neu-107, or dexamethasone as a control. Inflammatory cells and cytokines were assessed by bronchoalveolar lavage and histology. mRNA levels of endogenous antioxidant genes HO-1 and GCLm were determined by qPCR. Results. Cigarette smoke exposure induced acute lung inflammation with accumulation of neutrophils and upregulation of proinflammatory cytokines including IL-6, MIP-2 and KC. Both Neu-164 and Neu-107 significantly reduced the accumulation of inflammatory cells and the expression of inflammatory cytokines as effectively as dexamethasone. Upregulation of endogenous antioxidant genes was dampened. Conclusions. Neu-164 and Neu-107 inhibit acute cigarette smoke-induced inflammation by scavenging reactive oxygen species in cigarette smoke and by inhibiting further oxidative stress caused by inflammatory cells. These compounds may have promise in preventing or treating lung disease associated with chronic smoke exposure including COPD.
    No preview · Article · May 2013 · The American journal of physiology
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    ABSTRACT: Cigarette smoke is a profound pro-inflammatory stimulus that contributes to acute lung injuries and to chronic lung disease including COPD (emphysema and chronic bronchitis). Until recently, it was assumed that resolution of inflammation was a passive process that occurred once the inflammatory stimulus was removed. It is now recognized that resolution of inflammation is a bioactive process, mediated by specialized lipid mediators, and that normal homeostasis is maintained by a balance between pro-inflammatory and pro-resolving pathways. These novel small lipid mediators, including the resolvins, protectins and maresins, are bioactive products mainly derived from dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We hypothesize that resolvin D1 (RvD1) has potent anti-inflammatory and pro-resolving effects in a model of cigarette smoke-induced lung inflammation.
    No preview · Dataset · Mar 2013
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    ABSTRACT: Cigarette smoke is a profound pro-inflammatory stimulus that contributes to acute lung injuries and to chronic lung disease including COPD (emphysema and chronic bronchitis). Until recently, it was assumed that resolution of inflammation was a passive process that occurred once the inflammatory stimulus was removed. It is now recognized that resolution of inflammation is a bioactive process, mediated by specialized lipid mediators, and that normal homeostasis is maintained by a balance between pro-inflammatory and pro-resolving pathways. These novel small lipid mediators, including the resolvins, protectins and maresins, are bioactive products mainly derived from dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We hypothesize that resolvin D1 (RvD1) has potent anti-inflammatory and pro-resolving effects in a model of cigarette smoke-induced lung inflammation.
    Full-text · Article · Mar 2013 · PLoS ONE
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    ABSTRACT: Rationale: Cigarette smoke induced-chronic obstructive pulmonary disease (COPD) is a major global health issue with an increasing incidence worldwide. Inflammation plays an integral role in the development of COPD. Unresolved inflammatory responses can lead to substantial tissue injury, chronic inflammation and fibrosis. Current therapies only treat the disease symptoms and are limited in their ability to alter the course of the disease. Resolution of inflammatory responses was once believed to be passive, however, recent studies have shown that resolution is a biosynthetically active process involving endogenous pre-resolving lipid mediators, derived from omega-3 polyunsaturated fatty acids that control and limit inflammatory response. Resolvin D1 (RvD1) is an endogenous lipid mediator that displays potent anti-inflammatory and pro-resolving actions without being immunosuppressive. Therefore, we hypothesize that RvD1 might be a potential therapeutic in COPD to reduce inflammation while leaving the normal immune response intact. Methods: Mice were exposed to cigarette smoke for 3 days to induce acute lung inflammation, and were treated with RvD1 or vehicle by inhalation. The inflammatory response was evaluated by analysis of inflammatory cells and cytokines in bronchoalveolar lavage (BAL) and by Western blot and RT-PCR of cells and tissues. Results: Cigarette smoke-exposed mice treated with RvD1 exhibited a statistically significant 50% reduction of neutrophil accumulation in the BAL as well as significant reductions in the neutrophil chemoattractants KC and MIP-2. IL-6 and MCP-1 were also reduced. RvD1 treated lung tissue had reduced neutrophil infiltration with enhanced phagocytosis of apoptotic neutrophils by macrophages. Arg-1 and Mrc-1, markers of alternatively activated macrophages (M2) were upregulated in lung tissue homogenates and in BAL macrophages from smoke-exposed, RvD1-treated mice. Conclusion: RvD1 inhibited cigarette smoke-induced neutrophilic inflammation and promoted an anti-inflammatory and pro-resolving M2 phenotype among lung macrophages. This study provides insight into the therapeutic potential of w-3-PUFA-derived lipid mediators, and understanding the mechanism by which they counter-regulate inflammation may lead to the development of novel therapies to treat chronic inflammatory lung diseases such as COPD.
    No preview · Conference Paper · May 2011

  • No preview · Conference Paper · May 2011