Guirong Wang

State University of New York Upstate Medical University, Syracuse, New York, United States

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Publications (54)147.62 Total impact

  • Journal of Critical Care 08/2015; 30(4):827. DOI:10.1016/j.jcrc.2015.04.018 · 2.19 Impact Factor
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    ABSTRACT: Female mice exhibit a better survival rate than males after infection, but if infection follows an ozone-induced oxidative stress, male survival exceeds that of females. Our goal was to study bronchoalveolar lavage factors that contribute to these sex differences in outcome. We studied parameters at 4, 24, and 48 hours after ozone exposure and infection, including markers of inflammation, oxidative stress, and tissue damage, and surfactant phospholipids and surfactant protein A (SP-A). A multianalyte immunoassay at the 4 hr time point measured 59 different cytokines, chemokines, and other proteins. We found that: 1) Although some parameters studied revealed sex differences, no sex differences were observed in LDH, total protein, MIP-2, and SP-A. Males showed more intragroup significant differences in SP-A between filtered air- and ozone-exposed mice compared to females. 2) Oxidized dimeric SP-A was higher in FA-exposed female mice. 3) Surfactant phospholipids were typically higher in males. 4) The multianalyte data revealed differences in the exuberance of responses under different conditions - males in response to infection and females in response to oxidative stress. These more exuberant, and presumably less well-controlled responses associate with the poorer survival. We postulate that the collective effects of these sex differences in response patterns of lung immune cells may contribute to the clinical outcomes previously observed.
    Toxicology Letters 10/2014; 230(2). DOI:10.1016/j.toxlet.2014.04.008 · 3.36 Impact Factor
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    ABSTRACT: Sepsis is a major cause of acute kidney injury (AKI) with high rates of morbidity and mortality. Surfactant proteins A and D (SP-A, SP-D) play a critical role in host defense and regulate inflammation during infection. Recent studies indicate SP-A and SP-D are expressed in the kidney. The current study examines the role of SP-A and SP-D in the pathogenesis of sepsis-induced AKI. Wild-type (WT) and SP-A/SP-D double knockout (KO) C57BL/6 mice were treated by cecal ligation and puncture (CLP) or sham surgery. Histological, cellular and molecular indices of kidney injury were investigated in septic mice 6 and 24 h after CLP. 24 h post-CLP, kidney injury was more severe, renal function was decreased, blood creatinine and BUN were higher in septic SP-A/SP-D KO mice (p<0.05, vs septic WT mice). Kidney edema and vascular permeability were increased in septic SP-A/SP-D KO mice (p<0.01, vs septic WT mice). Apoptotic cells increased significantly (p<0.01) in the kidney of septic SP-A/SP-D KO mice compared to septic WT mice. Molecular analysis revealed levels of Bcl-2 (an inhibitor of apoptosis) were lower and levels of caspase-3 (a biomarker of apoptosis) were higher in the kidney of septic SP-A/SP-D KO mice (p<0.01, vs septic WT mice). Furthermore, levels of NF-κB and phosphorylated IκB-α increased significantly in the kidney of septic SP-A/SP-D KO mice than septic WT mice, suggesting SP-A/SP-D KO mice have a more pronounced inflammatory response to sepsis. We conclude SP-A and SP-D attenuate kidney injury by modulating inflammation and apoptosis in sepsis-induced AKI.
    Shock (Augusta, Ga.) 09/2014; 43(1). DOI:10.1097/SHK.0000000000000270 · 2.73 Impact Factor
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    ABSTRACT: We have demonstrated that specific synthetic maltose derivatives activate the swarming motility of a Pseudomonas aeruginosa nonswarming mutant (rhlA) at low concentration, but inhibit it at high concentration. Although these molecules are not microbicidal, active maltose derivatives with bulky hydrocarbon groups inhibited bacterial adhesion, and exhibited biofilm inhibition and dispersion (IC50 ∼20 μM and DC50 ∼30 μM, respectively). Because the swarming motility of the rhlA mutant is abolished by the lack natural rhamnolipids, the swarming activation suggests that maltose derivatives are analogues of rhamnolipids. Together, these results suggest a new approach of controlling multiple bacterial activities (bacterial adhesion, biofilm formation, and swarming motility) by a set of disaccharide-based molecules.
    ChemBioChem 07/2014; 15(10). DOI:10.1002/cbic.201402093 · 3.06 Impact Factor
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    ABSTRACT: Introduction: Acute respiratory distress syndrome (ARDS) is a common cause of organ failure with an associated mortality rate of 40%. The initiating event is disruption of alveolar-capillary interface causing leakage of edema into alveoli. Hypothesis: Electroporation-mediated gene delivery of epithelial sodium channel (ENaC) and Na+,K+-ATPase into alveolar cells would improve alveolar clearance of edema and attenuate ARDS. Methods: Pigs were anesthetized and instrumented, and the superior mesenteric artery was clamped to cause gut ischemia/reperfusion injury and peritoneal sepsis by fecal clot implantation. Animals were ventilated according to ARDSnet protocol. Four hours after injury, animals were randomized into groups: (i) treatment: Na+,K+-ATPase/ENaC plasmid (n = 5) and (ii) control: empty plasmid (n = 5). Plasmids were delivered to the lung using bronchoscope. Electroporation was delivered using eight-square-wave electric pulses across the chest. Following electroporation, pigs were monitored 48 h. Results: The Pao2/Fio2 ratio and lung compliance were higher in the treatment group. Lung wet/dry ratio was lower in the treatment group. Relative expression of the Na+,K+-ATPase transgene was higher throughout lungs receiving treatment plasmids. Quantitative histopathology revealed a reduction in intra-alveolar fibrin in the treatment group. Bronchoalveolar lavage showed increased surfactant protein B in the treatment group. Survival was improved in the treatment group. Conclusions: Electroporation-mediated transfer of Na+,K+-ATPase/ENaC plasmids improved lung function, reduced fibrin deposits, decreased lung edema, and improved survival in a translational porcine model of ARDS. Gene therapy can attenuate ARDS pathophysiology in a high-fidelity animal model, suggesting a potential new therapy for patients.
    Shock (Augusta, Ga.) 07/2014; 43(1). DOI:10.1097/SHK.0000000000000228 · 2.73 Impact Factor
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    ABSTRACT: In this study, we first generated and characterized a polyclonal antibody against unique domain of matrlin-2 and then used this specific antibody to assess the expression pattern of matrilin-2 by immunohistochemistry. We found that marilin-2 is widely distributed in the connective tissues of many mouse tissues including heart, colon, penis, esophagus, lung, kidney, tracheal cartilage, developmental bone, and adult bone. The expression level of matrilin-2 was remarkably increased in the tissues of osteoarthritis developmental articular cartilage, compared to normal healthy tissues. Furthermore, we determined matrilin-2 expression in specific epithelial cells in stomach and ductal epithelial cells of salivary gland. In other tissues, the positive signals were mainly located around cardiac muscle cells and Purkinje fibers in the heart; corpus spongiosum in the penis; submucosa in the colon and esophagus; extracellular matrix of cartilage in the tracheal cartilage; and, glomerulus, the basement membrane of distal convoluted tubule and renal matrix in kidney. These observations indicated that the distribution pattern of matrilin-2 is heterogeneous in each tissue. Matrilin-2 may play an important role in the communication of matrix to matrix and matrix to cells and will be used as a potential biomarker in the early stage of osteoarthritis of articular cartilage.
    03/2014; 2014:986127. DOI:10.1155/2014/986127
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    ABSTRACT: The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42-46°C and 50-55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia improves the abscopal antitumor effects, where localised irradiation of the tumor causes not only the irradiated tumor to shrink, but also tumors located far from the area of irradiation. Following induction of carcinosarcoma in both sides of the body, magnet-mediated hyperthermia was applied to one side only, leaving the other side as a control. The changes in tumor growth were observed. Our results demonstrated that magnet-mediated hyperthermia at a higher temperature inhibited the growth of carcinosarcoma at the site of treatment. Furthermore, the growth of the carcinosarcoma on the untreated side was also inhibited. The expression levels of proliferating cell nuclear antigen were decreased in the hyperthermia group, which was more significant in the higher temperature test group. Flow cytometric analysis showed an increased number of CD4- and CD8-positive T cells, and enzyme-linked immunosorbent assay showed increased levels of interferon-γ and interleukin-2 in the higher temperature group. These results suggested that magnet-mediated hyperthermia at a higher temperature (50-55°C) can improve the abscopal antitumor effects and stimulate a greater endogenous immune response in carcinosarcoma-bearing rats.
    Oncology letters 03/2014; 7(3):764-770. DOI:10.3892/ol.2014.1803 · 0.99 Impact Factor
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    ABSTRACT: Both natural and synthetic brominated furanones are known to inhibit biofilm formation by bacteria, but their toxicity to mammalian cells is often not reported. Here, we designed and synthesized a new class of brominated furanones (BBFs) that contained a bicyclic structure having one bromide group with well-defined regiochemistry. This class of molecules exhibited reduction in the toxicity to mammalian cells (human neuroblastoma SK-N-SH) and did not inhibit bacteria (Pseudomonas aeruginosa and Escherichia coli) growth, but retained the inhibitory activity towards biofilm formation of bacteria. In addition, all the BBFs inhibited the production of virulence factor elastase B in P. aeruginosa. To explore the effect of BBFs on quorum sensing, we used a reporter gene assay and found that 6-BBF and 7-BBF exhibited antagonistic activities for LasR protein in the lasI quorum sensing circuit, while 5-BBF showed agonistic activity for the rhlI quorum sensing circuit. This study suggests that structural variation of brominated furanones can be designed for targeted functions to control biofilm formation.
    Bioorganic & medicinal chemistry 01/2014; DOI:10.1016/j.bmc.2014.01.004 · 2.95 Impact Factor
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    ABSTRACT: Autophagy is a protective cellular mechanism in response to various stresses, including sepsis. Sepsis is defined as systemic inflammation by infection. Surfactant protein A and D (SP-A and SP-D) are involved in host defense, regulation of inflammation, and homeostasis, but their roles in the autophagic activity and relevant gene expression in sepsis are unclear. In this study, mice lacking SP-A and SP-D (SP-A/D KO mice) and background-matched wild-type (WT) C57BL/6 mice underwent either cecal ligation and puncture (CLP) or sham surgery. The results showed that SP-A/D KO mice had lower mortality than WT mice in CLP sepsis. Liver tissues showed marked pathological changes in both septic SP-A/D KO and WT mice 24 hrs after CLP treatment; and quantitative analysis of liver histopathology revealed significant difference between septic SP-A/D and septic WT mice. SP-A/D KO mice had higher basal and sepsis-induced level of autophagy than WT mice (p < 0.05), as judged by Western blot and electron microscopic analyses. The expression of 84 autophagy-related genes revealed differential basal and sepsis-induced gene expression between SP-A/D KO and WT mice. The expression increased in three genes and decreased in four genes in septic WT mice, as compared to septic SP-A/D KO mice (p < 0.05). Furthermore, differential responses to sepsis between SP-A/D KO and WT mice were found in six signaling pathways related to autophagy and apoptosis. Therefore, enhanced autophagic activity improves the survival of septic SP-A/D KO mice through the regulation of liver autophagy/apoptosis-related gene expression and signaling pathway activation.
    The Tohoku Journal of Experimental Medicine 10/2013; 231(2):127-138. DOI:10.1620/tjem.231.127 · 1.28 Impact Factor
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    ABSTRACT: IMPORTANCE Up to 25% of patients with normal lungs develop acute lung injury (ALI) secondary to mechanical ventilation, with 60% to 80% progressing to acute respiratory distress syndrome (ARDS). Once established, ARDS is treated with mechanical ventilation that can paradoxically elevate mortality. A ventilation strategy that reduces the incidence of ARDS could change the clinical paradigm from treatment to prevention. OBJECTIVES To demonstrate that (1) mechanical ventilation with tidal volume (Vt) and positive end-expiratory pressure (PEEP) settings used routinely on surgery patients causes ALI/ARDS in normal rats and (2) preemptive application of airway pressure release ventilation (APRV) blocks drivers of lung injury (ie, surfactant deactivation and alveolar edema) and prevents ARDS. DESIGN, SETTING, AND SUBJECTS Rats were anesthetized and tracheostomy was performed at State University of New York Upstate Medical University. Arterial and venous lines, a peritoneal catheter, and a rectal temperature probe were inserted. Animals were randomized into 3 groups and followed up for 6 hours: spontaneous breathing ventilation (SBV, n = 5), continuous mandatory ventilation (CMV, n = 6), and APRV (n = 5). Rats in the CMV group were ventilated with Vt of 10 cc/kg and PEEP of 0.5 cm H2O. Airway pressure release ventilation was set with a PHigh of 15 to 20 cm H2O; PLow was set at 0 cm H2O. Time at PHigh (THigh) was 1.3 to 1.5 seconds and a TLow was set to terminate at 75% of the peak expiratory flow rate (0.11-0.14 seconds), creating a minimum 90% cycle time spent at PHigh. Bronchoalveolar lavage fluid and lungs were harvested for histopathologic analysis at necropsy. RESULTS Acute lung injury/ARDS developed in the CMV group (mean [SE] Pao2/FiO2 ratio, 242.96 [24.82]) and was prevented with preemptive APRV (mean [SE] Pao2/FIO2 ratio, 478.00 [41.38]; P < .05). Airway pressure release ventilation also significantly reduced histopathologic changes and bronchoalveolar lavage fluid total protein (endothelial permeability) and preserved surfactant proteins A and B concentrations as compared with the CMV group. CONCLUSIONS AND RELEVANCE Continuous mandatory ventilation in normal rats for 6 hours with Vt and PEEP settings similar to those of surgery patients caused ALI. Preemptive application of APRV blocked early drivers of lung injury, preventing ARDS. Our data suggest that APRV applied early could reduce the incidence of ARDS in patients at risk.
    JAMA SURGERY 09/2013; 148(11). DOI:10.1001/jamasurg.2013.3746 · 4.30 Impact Factor
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    ABSTRACT: Once established, the acute respiratory distress syndrome (ARDS) is highly resistant to treatment and retains a high mortality. We hypothesized that preemptive application of airway pressure release ventilation (APRV) in a rat model of trauma/hemorrhagic shock (T/HS) would prevent ARDS. Rats were anesthetized, instrumented for hemodynamic monitoring, and subjected to T/HS, and randomized into two groups: 1) Volume Cycled Ventilation (VC) (n = 5, tidal volume 10ml/kg; PEEP 0.5 cmH2O) or 2) Airway Pressure Release Ventilation (APRV) (n = 4, PHigh 15-20 cmH2O; THigh 1.3-1.5 seconds to achieve 90% of the total cycle time; TLow 0.11-0.14 seconds which was set to 75% of the Peak Expiratory Flow rate; Plow 0 cmH2O). Study duration was six hours. ARPV prevented lung injury as measured by PaO2/FiO2 (VC 143.3 ± 42.4 vs. APRV 426.8 ± 26.9*, p<0.05), which correlated with a significant decrease in histopathology as compared with the VC group. In addition, APRV resulted in a significant decrease in bronchoalveolar lavage fluid (BALF) total protein, increased surfactant protein-B concentration, and an increase in E-cadherin tissue expression. In vivo microscopy demonstrated that APRV significantly improved alveolar patency and stability as compared to the VC group. Our findings demonstrate that preemptive mechanical ventilation with APRV attenuates the clinical and histologic lung injury associated with T/HS. The mechanism of injury prevention is related to preservation of alveolar epithelial and endothelial integrity. These data support our hypothesis that preemptive APRV, applied using published guidelines, can prevent the development of ARDS.
    Shock (Augusta, Ga.) 06/2013; 40(3). DOI:10.1097/SHK.0b013e31829efb06 · 2.73 Impact Factor
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    ABSTRACT: We have developed a novel class (2-amino-4-phenyl-4H-chromene-3-carboxylate) of inhibitors of tubulin assembly by modifying HA14-1, which is a Bcl-2 inhibitor discovered by our group. Three of these compounds, mHA1, mHA6, and mHA11, showed in vitro cytotoxicities against tumor cells that were more potent and more stable than authentic HA14-1, with IC50 values in the nM range. In contrast, cytotoxic effects of these mHAs on normal cells were slight. Computational docking, colchicine-tubulin competitive binding, and tubulin polymerization studies demonstrated that these compounds bind at the colchicine binding site on tubulin and inhibit the formation of microtubules. Treatment of HL-60/Bcl-2 leukemia and CRL5908 lung cancer cells with these mHAs led to pronounced microtubule density decreases, G2/M cell cycle arrest, and apoptosis, as determined by immunofluorescence microscopy, flow cytometry, and DNA fragmentation analysis. These results support the continued development of these compounds as potential anticancer agents.
    Molecular Cancer Research 05/2013; 11(8). DOI:10.1158/1541-7786.MCR-12-0177 · 4.50 Impact Factor
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    ABSTRACT: Surfactant protein A (SP-A) plays a number of roles in lung host defense and innate immunity. There are two human genes, SFTPA1 and SFTPA2, and evidence indicates that the function of SP-A1 and SP-A2 proteins differ in several respects. To investigate the impact of SP-A1 and SP-A2 on the alveolar macrophage (AM) phenotype, we generated humanized transgenic (hTG) mice on the SP-A knockout (KO) background, each expressing human SP-A1 or SP-A2. Using two-dimensional difference gel electrophoresis (2D-DIGE) we studied the AM cellular proteome. We compared mouse lines expressing high levels of SPA1, high levels of SP-A2, low levels of SP-A1, and low levels of SP-A2, with wild type (WT) and SP-A KO mice. AM from mice expressing high levels of SP-A2 were the most similar to WT mice, particularly for proteins related to actin and the cytoskeleton, as well as proteins regulated by Nrf2. The expression patterns from mouse lines expressing higher levels of the transgenes were almost the inverse of one another - the most highly expressed proteins in SP-A2 exhibited the lowest levels in the SP-A1 mice and vice versa. The mouse lines where each expressed low levels of SP-A1 or SP-A2 transgene had very similar protein expression patterns suggesting that responses to low levels of SP-A are independent of SP-A genotype, whereas the responses to higher amounts of SP-A are genotype-dependent. Together these observations indicate that in vivo exposure to SP-A1 or SP-A2 differentially affects the proteomic expression of AMs, with SP-A2 being more similar to WT.
    04/2013; 1(2):2-26. DOI:10.14302/issn.2326-0793.jpgr-12-207
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    ABSTRACT: The first half of the surfactant protein B (SP-B) gene intron 4 is a CA-repeat-rich region that contains 11 motifs. To study the role of this region on SP-B mRNA splicing, minigenes were generated by systematic removal of motifs from either the 5' or 3' end. These were transfected in CHO cells to study their splicing efficiency. The latter was determined as the ratio of completely to incompletely spliced SP-B RNA. Our results indicate that SP-B intron 4 motifs differentially affect splicing. Motifs 8 and 9 significantly enhanced and reduced splicing of intron 4, respectively. RNA mobility shift assays performed with a Motif 8 sequence that contains a CAUC cis-element and cell extracts resulted in a RNA:protein shift that was lost upon mutation of the element. Furthermore, in silico analysis of mRNA secondary structure stability for minigenes with and without motif 8 indicated a correlation between mRNA stability and splicing ratio. We conclude that differential loss of specific intron 4 motifs results in one or more of the following: a) altered splicing, b) differences in RNA stability and c) changes in secondary structure. These, in turn, may affect SP-B content in lung health or disease.
    02/2013; 2(1):40-55.
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    Jiao Liu · Fengqi Hu · Guirong Wang · Qingshan Zhou · Guohua Ding
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    ABSTRACT: Background Surfactant protein A (SP-A), encoded by two functional genes, SP-A1 and SP-A2, is essential for the inflammatory process and host defence in the lungs. Recent studies have demonstrated the extrapulmonary expression of SP-A. Similar to the lungs, the kidneys are organs exposed to external pathogens. The present study evaluated the expression and location of SP-A in the kidneys. The effect of lipopolysaccharide (LPS) on the expression of SP-A subtypes was also studied in renal tubular epithelial (HK-2) cells. Methods Immunohistochemical staining was performed using polyclonal antibody against SP-A. RT-PCR was also performed using mRNA from normal human renal tissues and HK-2 cells. The expressions of the SP-A1 and SP-A2 genes were determined by PCR-based RFLP analysis, gene-specific amplification, and direct sequencing of RT-PCR products. Western blot was conducted to analyse the SP-A protein. HK-2 cells were treated with LPS at various concentrations (0, 0.1, 1, 2, 5, and 10 μg/mL) for 8 h and at 5 μg/mL at various time points (0, 2, 4, 8, 16, and 24 h). The LPS-induced expressions of SP-A1 and SP-A2 mRNA and protein were analysed by RT-PCR and Western blot. Results SP-A was localised in the renal tubular epithelial cells in the proximal and distal convoluted tubules. SP-A1 and SP-A2 mRNA and protein were expressed in HK-2 cells and human renal tissues, which were significantly increased in time- and dose-dependent manners after LPS treatment (P < 0.05). Conclusions Human renal tubular epithelial cells can express both SP-A1 and SP-A2 genes, which may play important roles in the inflammatory modulation of the kidney.
    Journal of Inflammation 01/2013; 10(1):2. DOI:10.1186/1476-9255-10-2 · 2.22 Impact Factor
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    ABSTRACT: Acute respiratory distress syndrome (ARDS) afflicts 200,000 patients annually with a mortality rate of 30% to 60% despite wide use of low tidal volume (LTV) ventilation, the present standard of care. High-permeability alveolar edema and instability occur early in the development of ARDS, before clinical signs of lung injury, and represent potential targets for therapy. We hypothesize that early application of a protective ventilation strategy (airway pressure release ventilation [APRV]) will stabilize alveoli and reduce alveolar edema, preventing the development of ARDS. Yorkshire pigs (30-40 kg) were anesthetized and subjected to two-hit injury: (a) intestinal ischemia-reperfusion, (b) peritoneal sepsis, or sham surgery. Following surgery, pigs were randomized into APRV (n = 4), according to current published guidelines for APRV; LTV ventilation (n = 3), using the current published ARDS Network guidelines (6 mL/kg); or sham (n = 5). The clinical care of all pigs was administered per the Surviving Sepsis Campaign guidelines. Animals were killed, and necropsy performed at 48 h. Arterial blood gases were measured to assess for the development of clinical lung injury. Lung tissue epithelial cadherin (E-cadherin) was measured to assess alveolar permeability. Bronchoalveolar lavage fluid (BALF) surfactant protein A was measured to assess alveolar stability. Lung edema content and histopathology were analyzed at 48 h. Airway pressure release ventilation pigs did not develop ARDS. In contrast, pigs in the LTV ventilation met ARDS criteria (PaO2/FIO2 ratio) (APRV: baseline = 471 ± 16; 48 h = 392 ± 8; vs. LTV ventilation: baseline = 551 ± 28; 48 h = 138 ± 88; P < 0.001). Airway pressure release ventilation preserved alveolar epithelial integrity demonstrated by higher levels of E-cadherin in lung tissue as compared with LTV ventilation (P < 0.05). Surfactant protein A levels were higher in BALF from the APRV group, suggesting APRV preserved alveolar stability. Quantitative histologic scoring showed improvements in all stigmata of ARDS in the APRV group versus the LTV ventilation (P < 0.05). Airway pressure release ventilation had significantly lower lung edema (wet-dry weight) than LTV ventilation (P < 0.05). Protective ventilation with APRV immediately following injury prevents development of ARDS. Reduction in lung edema, preservation of lung E-cadherin, and surfactant protein A abundance in BALF suggest that APRV attenuates lung permeability, edema, and surfactant degradation. Protective ventilation could change the clinical paradigm from supportive care for ARDS with LTV ventilation to preventing development of ARDS with APRV.
    Shock (Augusta, Ga.) 01/2013; 39(1):28-38. DOI:10.1097/SHK.0b013e31827b47bb · 2.73 Impact Factor
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    ABSTRACT: Matrilin-2 (matn2) contains a unique domain, between the second von Willebrand factor A (vWFA) domain and the C-terminal coiled-coil domain, with no sequence homology with other family members. Complementary DNA (cDNA) sequence analysis of matn2 expression in both mice and humans revealed an alternative splice site in the region of the unique domain, which forms a short and a long splicing variant (containing an additional 19 amino acids). However, the expression heterogeneity of the alternative spliced variants, and the roles of the unique domain in oligomerization and proteolysis of matn2 are unknown. In this study, we examined the expression of the two alternative splice variants of matn2 in several skeletal and non-skeletal tissues by reverse transcription-polymerase chain reaction. Both splice variants of matn2 were detected at the mRNA level in all tissues studied. To explore the biochemical significance, several minigene constructs containing the second vWFA domain, the unique domain (with either a long or short form) and the coiled-coil domain of mouse mini matn2 were generated. Ectopic expression of these constructs demonstrated that the long form of matn2 is capable of self-assembling into several oligomeric forms, including a tetramer, trimer, pentamer or multimer; but the short form is only capable of forming a tetramer, trimer or dimer. Moreover, we observed that the splice variants of matn2 are important in modulating matn2 cleavage when co-expressed with matrilin-1 or matrilin-3. These results indicate that the two alternative splice variants have distinct roles in the processes of post-translational modification of matn2, which may have an impact on the homeostasis of the matrilin filamentous network of the extracellular matrix.
    Molecular Medicine Reports 08/2012; 6(5):1204-10. DOI:10.3892/mmr.2012.1056 · 1.48 Impact Factor
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    ABSTRACT: Established acute respiratory distress syndrome (ARDS) is often refractory to treatment. Clinical trials have demonstrated modest treatment effects, and mortality remains high. Ventilator strategies must be developed to prevent ARDS. Early ventilatory intervention will block progression to ARDS if the ventilator mode (1) maintains alveolar stability and (2) reduces pulmonary edema formation. Yorkshire pigs (38-45 kg) were anesthetized and subjected to a "two-hit" ischemia-reperfusion and peritoneal sepsis. After injury, animals were randomized into two groups: early preventative ventilation (airway pressure release ventilation [APRV]) versus nonpreventative ventilation (NPV) and followed for 48 hours. All animals received anesthesia, antibiotics, and fluid or vasopressor therapy as per the Surviving Sepsis Campaign. Titrated for optimal alveolar stability were the following ventilation parameters: (1) NPV group--tidal volume, 10 mL/kg + positive end-expiratory pressure - 5 cm/H2O volume-cycled mode; (2) APRV group--tidal volume, 10 to 15 mL/kg; high pressure, low pressure, time duration of inspiration (Thigh), and time duration of release phase (Tlow). Physiological data and plasma were collected throughout the 48-hour study period, followed by BAL and necropsy. APRV prevented the development of ARDS (p < 0.001 vs. NPV) by PaO₂/FIO₂ ratio. Quantitative histological scoring showed that APRV prevented lung tissue injury (p < 0.001 vs. NPV). Bronchoalveolar lavage fluid showed that APRV lowered total protein and interleukin 6 while preserving surfactant proteins A and B (p < 0.05 vs. NPV). APRV significantly lowered lung water (p < 0.001 vs. NPV). Plasma interleukin 6 concentrations were similar between groups. Early preventative mechanical ventilation with APRV blocked ARDS development, preserved surfactant proteins, and reduced pulmonary inflammation and edema despite systemic inflammation similar to NPV. These data suggest that early preventative ventilation strategies stabilizing alveoli and reducing pulmonary edema can attenuate ARDS after ischemia-reperfusion and sepsis.
    08/2012; 73(2):391-400. DOI:10.1097/TA.0b013e31825c7a82
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    ABSTRACT: Female mice exhibited higher survival rate than males after pneumonia, with a reversal of this pattern following ozone exposure. Surfactant protein A (SP-A) plays an important role in innate immunity and SP-A (-/-) mice were more susceptible to pneumonia than wild type mice. Here, we investigated underlying mechanisms of the differential susceptibility of mice to pneumonia. Wild type and SP-A (-/-) C57BL/6J male and female mice were exposed to ozone or filtered air (FA) and then infected intratracheally with Klebsiella pneumoniae. Blood, spleen, and lung were analyzed for bacterial counts, lung and spleen weights, and sex hormone and cortisol levels were measured in plasma within two days post-infection. We found: 1) in the absence of ozone-induced oxidative stress, males had higher level of bacterial dissemination compared to females; ozone exposure decreased pulmonary clearance in both sexes and ozone-exposed females were more affected than males; 2) ozone exposure increased lung weight, but decreased spleen weight in both sexes, and in both cases ozone-exposed females were affected the most; 3) plasma cortisol levels in infected mice changed: ozone-exposed>FA-exposed, females>males, and infected>non-infected; 4) no major sex hormone differences were observed in the studied conditions; 5) differences between wild type and SP-A (-/-) mice were observed in some of the studied conditions. We concluded that reduced pulmonary clearance, compromised spleen response to infection, and increased cortisol levels in ozone-exposed females, and the higher level of lung bacterial dissemination in FA-exposed males, contribute to the previously observed survival outcomes.
    Microbial Pathogenesis 04/2012; 52(4):239-49. DOI:10.1016/j.micpath.2012.01.005 · 2.00 Impact Factor
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    ABSTRACT: The genetic contribution to the development of bronchopulmonary dysplasia (BPD) in prematurely born infants is substantial, but information related to the specific genes involved is lacking. Genotype analysis revealed, after multiple comparisons correction, two significant single-nucleotide polymorphism (SNPs), rs3771150 (IL-18RAP) and rs3771171 (IL-18R1), in African Americans (AAs) with BPD (vs. AAs without BPD; q < 0.05). No associations with Caucasian (CA) BPD, AA or CA respiratory distress syndrome (RDS), or prematurity in either AAs or CAs were identified with these SNPs. Respective frequencies were 0.098 and 0.093 in infants without BPD and 0.38 for each SNP in infants with BPD. In the replication set (82 cases; 102 controls), the P values were 0.012 for rs3771150 and 0.07 for rs3771171. Combining P values using Fisher's method, overall P values were 8.31 × 10(-7) for rs3771150 and 6.33 × 10(-6) for rs3771171. We conclude that IL-18RAP and IL-18R1 SNPs identify AA infants at risk for BPD. These genes may contribute to AA BPD pathogenesis via inflammatory-mediated processes and require further study. We conducted a case-control SNP association study of candidate genes (n = 601) or 6,324 SNPs in 1,091 prematurely born infants with gestational age <35 weeks, with or without neonatal lung disease including BPD. BPD was defined as a need for oxygen at 28 days.
    Pediatric Research 01/2012; 71(1):107-14. DOI:10.1038/pr.2011.14 · 2.84 Impact Factor

Publication Stats

982 Citations
147.62 Total Impact Points

Institutions

  • 2011–2014
    • State University of New York Upstate Medical University
      • Department of Surgery
      Syracuse, New York, United States
  • 2000–2014
    • Penn State Hershey Medical Center and Penn State College of Medicine
      • • Pediatrics
      • • Cellular and Molecular Physiology
      Hershey, Pennsylvania, United States
  • 2013
    • University of Chicago
      Chicago, Illinois, United States
  • 2010–2011
    • William Penn University
      Hershey, Pennsylvania, United States
  • 2000–2009
    • Pennsylvania State University
      • • Department of Pediatrics
      • • Department of Cellular and Molecular Physiology
      University Park, Maryland, United States