Guirong Wang

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

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Publications (62)175.52 Total impact

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    ABSTRACT: Methods: WT and SP-A/D KO mice were subjected to S. aureus or sham pneumonia. Bronchoalveolar lavage and tissue harvest were performed 24 hours later. Pneumonia severity, gut mucosal injury, inflammation and apoptosis were measured using a combination of histology, immunohistochemistry, cytokine assay, TUNEL assay, qRT-PCR and Western blot analyses. Results: Pneumonia increased gut inflammation, apoptosis and mucosal injury in both groups. Pneumonia histology and bacterial growth in BAL fluid demonstrate more severe infection in SP-A/D KO mice compared to WT controls. SP-A/D KO mice with pneumonia also demonstrate more severe histologic gut mucosal injury, increased gut apoptosis, elevated caspase-3 levels and Bax/Bcl-2 mRNA expression compared with WT pneumonia mice. NF-κB p65 expression and its nuclear translocation, gut levels of TNF-α and IL-1β were all increased in SP-A/D KO mice with pneumonia compared to WT controls. Conclusions: These data provide evidence SP-A and SP-D attenuate S. aureus pneumonia severity resulting in decreased intestinal mucosal injury, apoptosis and inflammation. Improved pulmonary clearance of S. aureus, decreased caspase-3 and Bax/Bcl-2 expressions and decreased activation of the NF-κB signaling pathway in intestine represent potential mechanisms for the effects of SP-A and SP-D on gut injury during pneumonia.
    No preview · Article · Feb 2016 · Shock
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    ABSTRACT: Sepsis causes multiple-organ dysfunction including pancreatic injury, thus resulting in high mortality. Innate immune molecule surfactant protein D (SP-D) plays a critical role in host defense and regulating inflammation of infectious diseases. In this study we investigated SP-D functions in the acute pancreatic injury (API) with C57BL/6 Wild-type (WT) and SP-D knockout (KO) mice in cecal ligation and puncture (CLP) model. Our results confirm SP-D expression in pancreatic islets and intercalated ducts and are the first to explore the role of pancreatic SP-D in sepsis. CLP decreased pancreatic SP-D levels and caused severe pancreatic injury with higher serum amylase 24 h after CLP. Apoptosis and neutrophil infiltration were increased in the pancreas of septic KO mice (p < 0.05, vs septic WT mice), with lower Bcl-2 and higher caspase-3 levels in septic KO mice (p < 0.05). Molecular analysis revealed increased NF-κB-p65 and phosphorylated IκB-α levels along with higher serum levels of TNF-α and IL-6 in septic KO mice compared to septic WT mice (p < 0.01). Furthermore, in vitro islet cultures stimulated with LPS produced higher TNF-α and IL-6 (p < 0.05) from KO mice compared to WT mice. Collectively, these results demonstrate SP-D plays protective roles by inhibiting apoptosis and modulating NF-κB-mediated inflammation in CLP-induced API.
    Preview · Article · Dec 2015 · Scientific Reports
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    ABSTRACT: Lung injury is often studied without consideration for pathologic changes in the chest wall. In order to reduce the incidence of lung injury using preemptive mechanical ventilation, it is important to recognize the influence of altered chest wall mechanics on disease pathogenesis. In this study, we hypothesize that airway pressure release ventilation (APRV) may be able to reduce the chest wall elastance associated with an extrapulmonary lung injury model as compared with low tidal volume (LVt) ventilation. Female Yorkshire pigs were anesthetized and instrumented. Fecal peritonitis was established, and the superior mesenteric artery was clamped for 30 min to induce an ischemia/reperfusion injury. Immediately following injury, pigs were randomized into (1) LVt (n = 3), positive end-expiratory pressure (PEEP) 5 cmH 2 O, V t 6 cc kg −1 , F i O 2 21 %, and guided by the ARDSnet protocol or (2) APRV (n = 3), P High 16–22 cmH 2 O, P Low 0 cmH 2 O, T High 4.5 s, T Low set to terminate the peak expiratory flow at 75 %, and F i O 2 21 %. Pigs were monitored continuously for 48 h. Lung samples and bronchoalveolar lavage fluid were collected at necropsy. LVt resulted in mild acute respiratory distress syndrome (ARDS) (P a O 2 /F i O 2 = 226.2 ± 17.1 mmHg) whereas APRV prevented ARDS (P a O 2 /F i O 2 = 465.7 ± 66.5 mmHg; p < 0.05). LVt had a reduced surfactant protein A concentration and increased histologic injury as compared with APRV. The plateau pressure in APRV (34.3 ± 0.9 cmH 2 O) was significantly greater than LVt (22.2 ± 2.0 cmH 2 O; p < 0.05) yet transpulmonary pressure between groups was similar (p > 0.05). This was because the pleural pressure was significantly lower in LVt (7.6 ± 0.5 cmH 2 O) as compared with APRV (17.4 ± 3.5 cmH 2 O; p < 0.05). Finally, the elastance of the lung, chest wall, and respiratory system were all significantly greater in LVt as compared with APRV (all p < 0.05). APRV preserved surfactant and lung architecture and maintenance of oxygenation. Despite the greater plateau pressure and tidal volumes in the APRV group, the transpulmonary pressure was similar to that of LVt. Thus, the majority of the plateau pressure in the APRV group was distributed as pleural pressure in this extrapulmonary lung injury model. APRV maintained a normal lung elastance and an open, homogeneously ventilated lung without increasing lung stress.
    Full-text · Article · Dec 2015
  • Yongan Xu · Yucai Hong · Mengyan Xu · Kui Ma · Xiaobing Fu · Mao Zhang · Guirong Wang
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    ABSTRACT: Significance: There is growing evidence demonstrating a potential therapeutic application of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in injured skin. In the current study, conditioned media and chemically defined media with recombinant human keratinocyte growth factor (KGF) could induce hUC-MSC differentiation into sweat gland-like cells (SGCs). Moreover, the differentiated SGCs from hUC-MSCs could regenerate functional sparse sweat glands in a mouse burn model, which provides further insight into the mechanisms of the role of KGF and a potential therapeutic application of differentiated SGCs for regeneration of destroyed sweat glands and injured skin.
    No preview · Article · Nov 2015 · STEM CELLS TRANSLATIONAL MEDICINE
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    ABSTRACT: Staphylococcus aureus is a common cause of nosocomial pneumonia frequently resulting in acute respiratory distress syndrome (ARDS). Surfactant protein B (SP-B) gene expresses two proteins involved in lowering surface tension and host defense. Genotyping studies demonstrate a significant association between human SP-B genetic variants and ARDS. Curcumins have been shown to attenuate host inflammation in many sepsis models. Our hypothesis is that functional differences of SP-B variants and treatment with curcumin (CMC2.24) modulate lung injury in bacterial pneumonia. Humanized transgenic mice, expressing either SP-B T or C allele without mouse SP-B gene, were used. Bioluminescent labeled S. aureus Xen 36 (50 [mu]l) was injected intratracheally to cause pneumonia. Infected mice received daily CMC2.24 (40 mg/kg) or vehicle alone by oral gavage. Dynamic changes of bacteria were monitored using in vivo imaging system. Histological, cellular and molecular indices of lung injury were studied in infected mice 48 h after infection. In vivo imaging analysis revealed total flux (bacterial number) was higher in the lung of infected SP-B-C mice compared to infected SP-B-T mice (p < 0.05). Infected SP-B-C mice demonstrated increased mortality, lung injury, apoptosis and NF-[kappa]B expression compared to infected SP-B-T mice. Compared to controls, CMC2.24 treatment significantly reduced the following: mortality, total bacterial flux and lung tissue apoptosis, inflammatory cells, NF-[kappa]B expression (p < 0.05), and MMPs-2, -9, -12 activities (p < 0.05). We conclude that mice with SP-B-C allele are more susceptible to S. aureus pneumonia than mice with SP-B-T allele; and that CMC2.24 attenuates lung injury thus reducing mortality.
    No preview · Article · Nov 2015 · Shock
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    ABSTRACT: Surfactant protein B (SP-B) is essential for lung function. Previous studies have indicated that a SP-B 1580C/T polymorphism (SNP rs1130866) was associated with lung diseases including pneumonia. The SNP causes an altered N-linked glycosylation modification at Asn129 of proSP-B, e.g. the C allele with this glycosylation site but not in the T allele. This study aimed to generate humanized SP-B transgenic mice carrying either SP-B C or T allele without a mouse SP-B background and then examine functional susceptibility to bacterial pneumonia in vivo. A total of 18 transgenic mouse founders were generated by the DNA microinjection method. These founders were back-crossed with SP-B KO mice to eliminate mouse SP-B background. Four founder lines expressing similar SP-B levels to human lung were chosen for further investigation. After intratracheal infection with 50μl of P. aeruginosa solution (1X10(7) CFU/mouse) or saline in SP-B-C, SP-B-T mice the mice were sacrificed 24 hours post-infection and tissues were harvested. Analysis of surfactant activity revealed differential susceptibility between SP-B-C and SP-B-T mice to bacterial infection, e.g. higher minimum surface tension in infected SP-B-C versus infected SP-B-T mice. These results demonstrate for the first time that human SP-B C allele is more susceptible to bacterial pneumonia than SP-B T allele in vivo.
    No preview · Article · Nov 2015 · Biochemical and Biophysical Research Communications
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    ABSTRACT: To investigate the effects of surfactant proteins A and D (SP-A and SP-D, respectively) in urinary tract infection (UTI), SP-A and SP-D double knockout (SP-A/D KO) and wild type (WT) C57BL/6 female mice were infected with uropathogenic Escherichia coli by intravesical inoculation. Compared with WT mice SP-A/D KO mice showed increased susceptibility to UTI, as evidenced by higher bacterial CFU, more infiltrating neutrophils and severe pathological changes. Keratinocyte-derived chemokine increased in the kidney of WT mice but not in SP-A/D KO mice 24 h post-infection. Compared with control, the level of IL-17 was elevated in the kidney of infected WT and SP-A/D KO mice and the level of IL-17 was higher in the infected SP-A/D KO mice than in infected WT mice 24 and 48 h post-infection. The basal level of p38 MAPK phosphorylation in SP-A/D KO mice was higher than in WT mice. The phosphorylated p38 level was elevated in the kidney of WT mice post infection but not in SP-A/D KO mice. Furthermore, in vitro growth of uropathogenic E. coli was inhibited by SP-A and SP-D. We conclude that SP-A and SP-D function as mediators of innate immunity by inhibiting bacterial growth and modulating renal inflammation in part by regulating p38 MAPK-related pathway in murine UTI.
    No preview · Article · Oct 2015 · Innate Immunity
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    ABSTRACT: Staphylococcus aureus is one of the most common pathogens causing keratitis. Surfactant protein D (SP-D) plays a critical role in host defense and innate immunity. In order to investigate the role of SP-D in ocular S. aureus infection, the eyes of wild-type (WT) and SP-D knockout (SP-D KO) C57BL/6 mice were infected with S. aureus (107 CFU/eye) in the presence and absence of cysteine protease inhibitor(E64).Bacterial counts in the ocular surface were examined 3, 6, 12, 24 hrs after infection. Bacterial phagocytosis by neutrophils and bacterial invasion in ocular epithelial cells were evaluated quantitatively. S. aureus-induced ocular injury was determined with corneal fluorescein staining. The results demonstrated that SP-D is expressed in ocular surface epithelium and the lacrimal gland; WT mice had increased clearance of S. aureus from the ocular surface (p<0.05) and reduced ocular injury compared with SP-D KO mice. The protective effects of SP-D include increased bacterial phagocytosis by neutrophils (p<0.05) and decreased bacterial invasion into epithelial cells (p<0.05) in WT mice compared to in SP-D KO mice. In the presence of inhibitor (E64), WT mice showed enhanced bacterial clearance (p<0.05) and reduced ocular injury compared to absent E64 while SP-D KO mice did not. Collectively, we concluded that SP-D protects the ocular surface from S. aureus infection but cysteine protease impairs SP-D function in this murine model, and that cysteine protease inhibitor may be a potential therapeutic agent in S. aureus keratitis.
    Preview · Article · Sep 2015 · PLoS ONE

  • No preview · Article · Aug 2015 · Journal of Critical Care
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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.
    No preview · Article · Oct 2014 · Toxicology Letters
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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.
    No preview · Article · Sep 2014 · Shock (Augusta, Ga.)
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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.
    No preview · Article · Jul 2014 · ChemBioChem
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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.
    Full-text · Article · Jul 2014 · Shock (Augusta, Ga.)
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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.
    Full-text · Article · Mar 2014
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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.
    Full-text · Article · Mar 2014 · Oncology letters
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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.
    No preview · Article · Jan 2014 · Bioorganic & medicinal chemistry
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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.
    No preview · Article · Oct 2013 · The Tohoku Journal of Experimental Medicine
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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.
    Full-text · Article · Sep 2013 · JAMA SURGERY
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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.
    Full-text · Article · Jun 2013 · Shock (Augusta, Ga.)
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    ABSTRACT: Unlabelled: 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 the backbone compound HA14-1, with nM IC50 values. In contrast, the cytotoxic effects of these compounds on normal cells were minimal. 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 mHA compounds led to pronounced microtubule density decreases, G2/M cell cycle arrest, and apoptosis, as determined by immunofluorescence microscopy, flow cytometry, and DNA fragmentation analysis. Combined, these data identify a novel class of compounds that inhibit tubulin assembly and limit cancer cell phenotypes. Implications: This study supports the continued development of novel anti-tubulin assembly inhibitors as potential anticancer agents.
    Preview · Article · May 2013 · Molecular Cancer Research

Publication Stats

1k Citations
175.52 Total Impact Points

Institutions

  • 2011-2015
    • State University of New York Upstate Medical University
      • Department of Surgery
      Syracuse, New York, United States
  • 2002-2014
    • 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