Krishnan Raghavendran

Roswell Park Cancer Institute, Buffalo, NY, United States

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Publications (60)153.71 Total impact

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    ABSTRACT: Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. Hypoxia-inducible factor-1α is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension. We set to determine if hypoxia-inducible factor-1α plays a role in the pathogenesis of acute inflammatory response and injury in lung contusion.
    Critical Care Medicine 07/2014; · 6.12 Impact Factor
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    ABSTRACT: Pulmonary aspiration is an important recognized cause of acute respiratory distress syndrome (ARDS). Better characterization of patients who aspirate may allow identification of potential risks for aspiration that could be used in future studies to mitigate the occurrence of aspiration and its devastating complications. We conducted a secondary analysis of the Lung Injury Prediction Score (LIPS) cohort to better characterize patients with aspiration, including their potential risk factors and related outcomes. Of the 5584 subjects at risk for ARDS and required hospitalization, 212 (3.8%) presented with aspiration. Subjects who aspirated were likely to be male (66% vs. 56%, p<0.007), slightly older (59 vs. 57years), Caucasian (73% vs. 61%, p=0.0004), admitted from a nursing-home (15% vs. 5.9%, p<0.0001), have a history of alcohol abuse (21% vs. 8%, p<0.0001) and have lower Glasgow Coma Scale (median 13 vs. 15, p<0.0001). Aspiration subjects were sicker (higher APACHE2), required more mechanical ventilation (54% vs. 32%, p<0.0001), developed more moderate-to-severe ARDS (12% vs. 3.8%, p<0.0001), and were two-fold more likely to die in-hospital, even after adjustment for severity of illness (OR=2.1; 95%CI: 1.2-3.6). Neither obesity nor gastroesophageal-reflux was associated with aspiration. Aspiration was more common in men, with alcohol abuse history, a lower GCS, and when admitted from a nursing home. It is independently associated with a significant increase in the risk for ARDS as well as morbidity and mortality. Findings from this study may facilitate the design of future clinical studies of aspiration-induced lung injury.
    Chest 05/2014; · 7.13 Impact Factor
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    ABSTRACT: Lung contusion (LC) is a common injury resulting from blunt thoracic trauma. LC is an important risk factor for the development acute lung injury, adult respiratory distress syndrome, and ventilator-associated pneumonia, all of which increase mortality from trauma. LC produces a nonspecific immune cellular response. Neutrophil recruitment is known to increase the severity of inflammation during LC. However, the exact role of macrophages in modulating the response to LC has not been well described. We used a cortical contusion impactor to induce unilateral LC in mice. Thoracic micro computed tomographic scans of these animals were obtained to document radiologic changes over time following LC. To understand the role of macrophages during LC, liposomal clodronate was used to deplete macrophage levels before traumatic insult. Acute inflammatory attributes after LC were assessed, by measuring pressure-volume mechanics; quantifying bronchial alveolar lavage levels of leukocytes, albumin, and cytokines; and finally examining lung specimen histopathology at 5, 24, 48, and 72 hours after injury. After LC, alveolar macrophage numbers were significantly reduced and exhibited slowed recovery. Simultaneously, there was a significant increase in bronchial alveolar lavage neutrophil counts. The loss of macrophages could be attributed to both cellular apoptosis and necrosis. Pretreatment with clodronate increased the severity of lung inflammation as measured by worsened pulmonary compliance, increased lung permeability, amplification of neutrophil recruitment, and increases in early proinflammatory cytokine levels. The presence of regulatory alveolar macrophages plays an important role in the pathogenesis of acute inflammation following LC.
    The journal of trauma and acute care surgery. 04/2014; 76(4):982-90.
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    ABSTRACT: Lung contusion injury produces a vulnerable window within the inflammatory defenses of the lung that predisposes the patient to pneumonia. IL-10 is a known anti-inflammatory mediator produced by macrophages and capable of down-regulating acute lung inflammation. We investigated the impact of increased levels of IL-10 within the lung on survival and the host response to trauma in the setting of lung contusion and Gram-negative pneumonia. A bi-transgenic, tetracycline inducible, lung specific human IL-10 overexpression (IL-10 OE) mouse model and single transgenic (TG-) control mice were used. Mice underwent lung contusion injury (LC) or sham injury (Sham) at time -6 hrs. At time 0 animals were inoculated intratracheally with 500 CFU of Klebsiella pneumoniae (Pneu). Bronchoalveolar lavage fluid (BAL), lung tissue specimens, or purified macrophages were collected. Lung tissue and blood bacteria levels were quantified. Cytokine levels were assayed by ELISA and gene expression levels were evaluated by real time PCR. Cell type identification and quantification was done using real time PCR and flow cytometry. IL-10 OE mice demonstrated decreased 5 day survival compared to TG- mice following LC+Pneu (0 vs. 30%, p<0.0001). IL-10 OE mice had significantly higher lung bacteria counts (p=0.02) and levels of bacteremia (p=0.001) at 24 hrs. The IL-10 OE mice recruited more neutrophils into the alveoli as measured in BAL fluid compared to TG- mice. Alveolar macrophages from IL-10 OE mice displayed increased alternative activation (M2 macrophages, p=0.046) whereas macrophages from TG- mice exhibited classical activation (M1 macrophages) and much higher intracellular bacterial killing potential (p=0.03). IL-6, KC, and MIP-2 levels were significantly elevated in IL-10 OE LC+Pneu animals (p<0.05). Lung specific IL-10 over expression induces alternative activation of alveolar macrophages. This shift in macrophage phenotype decreases intracellular bacterial killing, resulting in a more pronounced bacteremia and accelerated mortality in a model of lung contusion and pneumonia.
    Shock (Augusta, Ga.) 01/2014; · 2.87 Impact Factor
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    ABSTRACT: Cholesterol synthesis is a highly oxygen dependent process. Paradoxically, hypoxia is correlated with an increase in cellular and systemic cholesterol levels and risk of cardiovascular diseases. The mechanism for the increase in cholesterol during hypoxia is unclear. Hypoxia signaling is mediated through hypoxia-inducible factor (HIF)-1α and HIF-2α. The present study demonstrates that activation of HIF signaling in the liver increases hepatic and systemic cholesterol levels due to a decrease in the expression of cholesterol hydroxylases CYP7A1 and other enzymes involved in bile acid synthesis. Specifically, activation of hepatic HIF-2α (but not HIF-1α) led to hypercholesterolemia. HIF-2α repressed the circadian expression of Rev-erbα resulting in increased expression of E4BP4, a negative regulator of Cyp7a1. To understand if HIF-mediated decrease in bile acid synthesis is a physiological relevant pathway by which hypoxia maintains or increases systemic cholesterol levels, two hypoxic mouse models were assessed; an acute lung injury model and mice exposed to 10% O2 for three weeks. In both the models cholesterol levels increased with a concomitant decrease in expression of genes involved in bile acid synthesis. The present study demonstrates that hypoxic activation of hepatic HIF-2α leads to an adaptive increase in cholesterol levels through inhibition of bile acid synthesis.
    Molecular and cellular biology 01/2014; · 6.06 Impact Factor
  • David Machado-Aranda, Krishnan Raghavendran
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    ABSTRACT: Several of the biological processes involved in the pathogenesis of acute lung injury and acute respiratory distress syndrome after lung contusion are regulated at a genetic and epigenetic level. Thus, strategies to manipulate gene expression in this context are highly desirable not only to elucidate the mechanisms involved but also to look for potential therapies. In the present chapter, we describe mouse and rat models of inducing blunt thoracic injury followed by electroporation-mediated gene delivery to the lung. Electroporation is a highly efficient and easily reproducible technique that allows circumvention of several of lung gene delivery challenges and safety issues present with other forms of lung gene therapy.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1121:205-21. · 1.29 Impact Factor
  • Douglas L. Miller, M.V. Suresh, Chunyan Dou, B. Yu, Krishnan Raghavendran
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    ABSTRACT: Routine pulmonary ultrasound for diagnosis of disease or injury relies on interpretation of image features, such as comet-tail artifacts, which can also be indicative of the poorly understood phenomenon of ultrasound-induced pulmonary capillary hemorrhage (PCH). Evans blue extraction and bronchoalveolar lavage (BAL) were evaluated for assessment of PCH induced by ultrasound scanning. Rats anesthetized with ketamine with or without xylazine received sham or scanning for 5 min with a 7.6 MHz linear array. Evans blue extraction and BAL albumin measurements failed to demonstrate significant increases for scanning, even though the induction of comet-tail artifacts was significant. BAL cell counts had an insignificant increase relative to shams at a near-threshold Mechanical Index (MI) of 0.52 (P = 0.07), but a highly significant increase at MI = 0.9 (P = 0.001). The possibility of xylazine-induced elevated albumin was tested, but no significant decrease was found for sham or scanned rats with ketamine-only anesthesia. Interestingly, without xylazine, the widths of comet-tail artifacts in the ultrasound images were significantly smaller (P = 0.001) and cell counts in BAL fluid also were reduced (P = 0.014). The BAL cell-count method provides a valuable additional means of PCH quantification.
    Microvascular Research 01/2014; · 2.93 Impact Factor
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    ABSTRACT: Lung contusion (LC) is a unique direct and focal insult that is considered a major risk factor for the initiation of acute lung injury and acute respiratory distress syndrome. We have shown recently that consumption of nitric oxide (due to excess superoxide) resulting in peroxynitrite formation leads to decreased vascular reactivity after LC. In this study, we set out to determine whether the superoxide scavenger Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) plays a protective role in alleviating acute inflammatory response and injury in LC. Nonlethal, closed-chest, bilateral LC was induced in a rodent model. Administration of the superoxide dismutase mimetic MnTBAP concurrently in LC in rats was performed, and bronchoalveolar lavage (BAL) and lung samples were analyzed for degree of injury and inflammation at 5 and 24 h after the insult. The extent of injury was assessed by the measurement of cells and albumin with cytokine levels in the BAL and lungs. Lung samples were subjected to H&E and superoxide staining with dihydro-ethidium. Protein-bound dityrosine and nitrotyrosine levels were quantified in lung tissue by tandem mass spectrometry. The degrees of lung injury after LC as determined by BAL albumin levels were significantly decreased in the MnTBAP-administered rats at all the time points when compared to the corresponding controls. The release of proinflammatory cytokines and BAL neutrophils was significantly less in the rats administered MnTBAP after LC. Administration of MnTBAP decreased tissue damage and decreased necrosis and neutrophil-rich exudate at the 24-h time point. Staining for superoxide anions showed significantly greater intensity in the lung samples from the LC group compared to the LC+ MnTBAP group. High-performance liquid chromatography/tandem mass spectrometry revealed that MnTBAP treatment significantly attenuated dityrosine and nitrotyrosine levels, consistent with decreased oxidant injury. Superoxide dismutase mimetic-MnTBAP reduced permeability and oxidative injury in LC and may have a therapeutic role in diminishing inflammation in LC.
    Surgery 11/2013; 154(5):980-90. · 3.37 Impact Factor
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    ABSTRACT: BACKGROUND:: Acute lung injury (ALI) is associated with high mortality. Low tidal volume (Vt) ventilation has been shown to reduce mortality in ALI patients in the intensive care unit. Anesthesiologists do not routinely provide lung-protective ventilation strategies to patients with ALI in the operating room. The authors hypothesized that an alert, recommending lung-protective ventilation regarding patients with potential ALI, would result in lower Vt administration. METHODS:: The authors conducted a randomized controlled trial on anesthesia providers caring for patients with potential ALI. Patients with an average or last collected ratio of partial pressure of arterial oxygen to inspired fraction of oxygen less than 300 were randomized to providers being sent an alert with a recommended Vt of 6 cc/kg predicted body weight or conventional care. Primary outcomes were Vt/kg predicted body weight administered to patients. Secondary outcomes included ventilator parameters, length of postoperative ventilation, and death. RESULTS:: The primary outcome was a clinically significant reduction in mean Vt from 508-458 cc (P = 0.033), with a reduction in Vt when measured in cc/kg predicted body weight from 8 to 7.2 cc/kg predicted body weight (P = 0.040). There were no statistically significant changes in other outcomes or adverse events associated with either arm. CONCLUSIONS:: Automated alerts generated for patients at risk of having ALI resulted in a statistically significant reduction in Vt administered when compared with a control group. Further research is required to determine whether a reduction in Vt results in decreased mortality and/or postoperative duration of mechanical ventilation.
    Anesthesiology 05/2013; · 5.16 Impact Factor
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    ABSTRACT: Interstitial lung fibrosis can develop as a consequence of occupational or medical exposures, as a result of genetic defects, following trauma or acute lung injury leading to fibroproliferative acute respiratory distress syndrome (ARDS) or can develop in an idiopathic manner. The pathogenesis of each of these forms of lung fibrosis is poorly understood. They each result in progressive loss of lung function with increasing dyspnea and ultimately, most forms result in mortality. To better understand the pathogenesis of lung fibrotic disorders, multiple animal models have been developed. This review summarizes common and emerging models of lung fibrosis to highlight their usefulness for understanding cell-cell and soluble mediator interactions which drive fibrotic responses. Recent advances have allowed for development of models to study targeted injury of type II alveolar epithelial cells, fibroblast autonomous effects and targeted genetic defects. Repetitive dosing in some models has more closely mimicked the pathology of human fibrotic lung disease. We also have a much better understanding of the fact that the aged lung increases susceptibility to fibrosis. Each of these models reviewed in this report offer a powerful tool to study some aspect of fibrotic lung disease.
    American Journal of Respiratory Cell and Molecular Biology 03/2013; · 4.15 Impact Factor
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    ABSTRACT: RATIONALE: The mechanisms contributing to hypoxia in lung contusion remain unclear and not temporally associated with the peak onset of acute inflammation. OBJECTIVE: We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. Additionally, the role of antioxidants in reversing this process was examined. METHODS: PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a NO synthase (NOS) inhibitor, L-nitro arginine (LNA 10 M) or PEG-superoxide dismutase (SOD) and PEG-catalase (CAT) or both (LNA+SOD/CAT). Rings were constricted with norepinephrine (NE) and relaxed with an NOS agonist (A23187) or NO donor (SNAP). Immunochemical and mass spectrometric quantification for nitrotyrosine were performed. RESULTS: Rats were hypoxemic at 4h post-contusion compared to controls, but recovered by 24h (PaO2/FiO2 ratio: baseline- 443+28, 4h-288+46 and 24h-417+23). PA constriction to NOS inhibition and relaxation to A23187 were impaired 4h after LC. PA relaxation to SNAP was decreased at 4h and 24h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA was up-regulated and soluble guanylyl cyclase (sGC) mRNA was down-regulated 24h after LC. IHC and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4h following LC consistent with superoxide generation and formation of peroxynitrite. CONCLUSION: Collectively, this data suggests that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC.
    Shock (Augusta, Ga.) 01/2013; · 2.87 Impact Factor
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    ABSTRACT: Recruitment of neutrophils and release of reactive oxygen species are considered to be major pathogenic components driving acute lung injury (ALI). However, NADPH oxidase, the major source of reactive oxygen species in activated phagocytes, can paradoxically limit inflammation and injury. We hypothesized that NADPH oxidase protects against ALI by limiting neutrophilic inflammation and activating Nrf2, a transcriptional factor that induces antioxidative and cytoprotective pathways. Our objective was to delineate the roles of NADPH oxidase and Nrf2 in modulating acute lung inflammation and injury in clinically relevant models of acute gastric aspiration injury, a major cause of ALI. Acid aspiration caused increased ALI (as assessed by bronchoalveolar lavage fluid albumin concentration) in both NADPH oxidase-deficient mice and Nrf2(-/-) mice compared with wild-type mice. NADPH oxidase reduced airway neutrophil accumulation, but Nrf2 decreased ALI without affecting neutrophil recovery. Acid injury resulted in a 120-fold increase in mitochondrial DNA, a proinflammatory and injurious product of cellular necrosis, in cell-free bronchoalveolar lavage fluid. Pharmacologic activation of Nrf2 by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9 (11)-dien-28-oyl]imidazole limited aspiration-induced ALI in wild-type mice and reduced endothelial cell injury caused by mitochondrial extract-primed human neutrophils, leading to the conclusion that NADPH oxidase and Nrf2 have coordinated, but distinct, functions in modulating inflammation and injury. These results also point to Nrf2 as a therapeutic target to limit ALI by attenuating neutrophil-induced cellular injury.
    The Journal of Immunology 01/2013; · 5.52 Impact Factor
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    ABSTRACT: Despite the prevalence of blunt hepatic trauma in humans, there are few rodent models of blunt trauma that can be used to study the associated inflammatory responses. We present a mouse model of blunt hepatic trauma that was created by using a cortical contusion device. Male mice were anesthetized with ketamine-xylazine-buprenorphine and placed in left lateral recumbency. A position of 2 mm ventral to the posterior axillary line and 5 mm caudal to the costal margin on the right side was targeted for impact. An impact velocity of 6 m/s and a piston depth of 12 mm produced a consistent pattern of hepatic injury with low mortality. All mice that recovered from anesthesia survived without complication for the length of the study. Mice were euthanized at various time points (n = 5 per group) until 7 d after injury for gross examination and collection of blood and peritoneal lavage fluids. Some mice were reanesthetized for serial monitoring of hepatic lesions via MRI. At 2 h after trauma, mice consistently displayed laceration, hematoma, and discoloration of the right lateral and caudate liver lobes, with intraabdominal hemorrhage but no other gross injuries. Blood and peritoneal lavage fluid were collected from all mice for cytokine analysis. At 2 h after trauma, there were significant increases in plasma IL10 as well as peritoneal lavage fluid IL6 and CXCL1/KC; however, these levels decreased within 24 h. At 7 d after trauma, the mice had regained body weight, and the hepatic lesions, which initially had increased in size during the first 48 h, had returned to their original size. In summary, this technique produced a reliable, low mortality, murine model that recreates features of blunt abdominal liver injury in human subjects with similar acute inflammatory response.
    Comparative medicine 01/2013; 63(5):398-408. · 1.12 Impact Factor
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    ABSTRACT: It is not clear why some patients with aspiration advance to acute lung injury or acute respiratory distress syndrome, whereas others do not. The Western diet is high in advanced glycation end products (AGEs) which have been found to be proinflammatory. We hypothesize that dietary AGEs exaggerate the pulmonary inflammatory response following gastric aspiration. CD-1 mice were randomized to receive either a low (LAGE) or a high AGE (HAGE) diet for four weeks. Five hours after intratracheal instillation of acidified small gastric particles, pulmonary function was determined. Polymorphonuclear leukocyte (PMNs) counts, albumin, cytokine/chemokine, and TNF soluble receptor II (TNFsRII) concentrations in the bronchoalveolar lavage (BAL) and lung myeloperoxidase (MPO) activity were measured. Compared to LAGE-fed animals, those fed a HAGE diet had increased lung tissue resistance (p = .017), BAL albumin concentration (p < 0.05), pulmonary PMN counts (p = 0.0045), and lung MPO activity (p = .002) following aspiration. In addition, the plasma levels of TNFsRII were significantly elevated (p < 0.05), while paradoxically levels of keratinocyte chemoattractant (KC) and monocyte chemoattractant protein-1 (MCP-1) were decreased in mice with HAGE diet. In conclusion, a diet high in AGEs exacerbates acute lung injury following gastric aspiration as evidenced by increases in neutrophil infiltration, airway albumin leakage, and decreased pulmonary compliance. This is the first evidence implicating exacerbation of acute inflammatory lung injury by dietary AGEs. Targeting AGEs in the circulatory system may offer a therapeutic strategy for limiting lung injury following gastric aspiration.
    Shock (Augusta, Ga.) 11/2012; · 2.87 Impact Factor
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    ABSTRACT: OBJECTIVE: Surfactant dysfunction is an important pathologic disturbance in various forms of acute inflammatory lung injury. Previously we reported the presence of marked alterations in the composition and activity of pulmonary surfactant in bilateral lung contusions (LC) injury induced by blunt trauma in rats. This is extended here to a mouse model of unilateral LC with a focus on compositional and functional changes in surfactant associated with permeability injury and increases in activity of secretory phospholipase A(2). RESULTS: Surfactant-associated gene expression was not altered in mice with unilateral LC injury on the basis of Affymetrix analysis. LC mice had significant permeability injury with increased albumin and total protein in bronchoalveolar lavage at 5, 24, 48, and 72 hours after insult compared with uninjured controls. The percent content of large surfactant aggregates was depleted at all postinjury times, and pulmonary pressure-volume (P-V) mechanics and compliance were abnormal during this period. Surfactant dysfunction was evaluated in 24 hours, when permeability injury and P-V changes were most prominent. At this time, activity levels of secretory phospholipase A(2) were increased in bronchoalveolar lavage, and chromatographic analysis showed that large surfactant aggregates had decreased levels of phosphatidylcholine and increased levels of lyso-phosphatidylcholine. These changes were accompanied by severe detriments in large aggregate surface activity by pulsating bubble surfactometry. Large aggregates from LC mice at 24 hours had minimum surface tensions of only 12.6 ± 1.1 mN/m after prolonged bubble pulsation (20 min) compared with 0.7 ± 0.03 mN/m for uninjured controls. CONCLUSION: These results document important detriments in the composition and activity of pulmonary surfactant in LC injury in mice and suggest that active synthetic phospholipase-resistant exogenous surfactants may have utility in treating surfactant dysfunction in this clinically important condition.
    Surgery 07/2012; · 3.37 Impact Factor
  • Weidun Alan Guo, Paul R Knight, Krishnan Raghavendran
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    ABSTRACT: The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor and evolutionary member of the immunoglobulin superfamily that is involved in the host response to infection, injury, and inflammation. It exists in two forms: membrane-bound and soluble forms (sRAGE). RAGE recognizes a variety of ligands and, via a receptor-driven signaling cascade, activates the transcription factor NF-κB, leading to the expression of proinflammatory cytokines. The soluble form, sRAGE, is a decoy receptor and competitively inhibits membrane RAGE activation. RAGE is constitutively expressed abundantly in the lung under basal conditions. This expression is enhanced during inflammatory states such as with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). This review summarizes the characteristics of RAGE, RAGE isoforms, RAGE ligands, and signaling pathways in the pathogenesis of ALI and ARDS. Additionally, the review explores the potential of RAGE as an important therapeutic target in ALI/ARDS.
    European Journal of Intensive Care Medicine 07/2012; 38(10):1588-98. · 5.17 Impact Factor
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    ABSTRACT: Lung contusion (LC) induces inflammation with high local concentrations of proinflammatory mediators stimulating chemotaxis and activation of neutrophils. LC is also a risk factor for development of pneumonia; however, the reason for this increased susceptibility is not clearly identified. We hypothesize that LC creates acute changes in the host pulmonary innate immune system that leads to vulnerability from a "second" hit bacterial infection. Female C57Bl/6 mice underwent LC injury at time -6 hours. At 0 hours, these mice were inoculated intratracheally with 1,000 colony forming unit (CFU) of Klebsiella pneumoniae (LC+Pneu) or vehicle (LC). Control animals underwent a sham LC injury followed by pneumonia (Sham+Pneu). Bronchoalveolar lavage (BAL) fluid and lung tissue specimens were collected. Lung bacteria levels were quantified by serial dilution, plating, and counting CFUs. Cytokine levels were assayed by ELISA. Cell type identification and quantification was performed using flow cytometry. Survival at 72 hours was markedly different for the LC, Sham+Pneu, and LC+Pneu groups (100%, 80%, 20%, p < 0.05 Sham+Pneu vs. LC+Pneu). LC+Pneu animals had decreased pulmonary bacterial clearance at 24 hours compared with the Sham+Pneu group (4 × 10(7) vs. 8 × 10(6) CFUs, p < 0.05). BAL levels of IL-1β, IL-6, and keratinocyte chemoattractant were all significantly elevated in LC+Pneu mice compared with the Sham+Pneu group at 24 hours. Conversely, the Sham+Pneu mice had increased levels of macrophage inflammatory protein-2, total cells, macrophages, and neutrophils in BAL compared with the LC+Pneu group at 24 hours. LC+Pneu animals demonstrated changes in macrophage apoptosis and necrosis in BAL samples obtained 2 hours after induction of pneumonia when compared with the Sham+Pneu group. Both Sham+Pneu and LC+Pneu animals demonstrated an increase in the level of IL-10 in BAL fluid compared with LC animals. Acute inflammation after LC acts to modulate the presence of inflammatory cells necessary to combat gram-negative bacteria. This results in decreased bacterial clearance and increased mortality from pneumonia.
    The journal of trauma and acute care surgery. 03/2012; 72(3):614-22; discussion 622-3.
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    ABSTRACT: Lung contusion (LC), commonly observed in patients with thoracic trauma is a leading risk factor for development of acute lung injury/acute respiratory distress syndrome. Previously, we have shown that CC chemokine ligand (CCL)-2, a monotactic chemokine abundant in the lungs, is significantly elevated in LC. This study investigated the nature of protection afforded by CCL-2 in acute lung injury/acute respiratory distress syndrome during LC, using rats and CC chemokine receptor (CCR) 2 knockout (CCR2(-/-)) mice. Rats injected with a polyclonal antibody to CCL-2 showed higher levels of albumin and IL-6 in the bronchoalveolar lavage and myeloperoxidase in the lung tissue after LC. Closed-chest bilateral LC demonstrated CCL-2 localization in alveolar macrophages (AMs) and epithelial cells. Subsequent experiments performed using a murine model of LC showed that the extent of injury, assessed by pulmonary compliance and albumin levels in the bronchoalveolar lavage, was higher in the CCR2(-/-) mice when compared with the wild-type (WT) mice. We also found increased release of IL-1β, IL-6, macrophage inflammatory protein-1, and keratinocyte chemoattractant, lower recruitment of AMs, and higher neutrophil infiltration and phagocytic activity in CCR2(-/-) mice at 24 hours. However, impaired phagocytic activity was observed at 48 hours compared with the WT. Production of CCL-2 and macrophage chemoattractant protein-5 was increased in the absence of CCR2, thus suggesting a negative feedback mechanism of regulation. Isolated AMs in the CCR2(-/-) mice showed a predominant M1 phenotype compared with the predominant M2 phenotype in WT mice. Taken together, the above results show that CCL-2 is functionally important in the down-modulation of injury and inflammation in LC.
    American Journal of Respiratory Cell and Molecular Biology 01/2012; 46(6):797-806. · 4.15 Impact Factor
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    David A Machado-Aranda, M V Suresh, Bi Yu, Krishnan Raghavendran
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    ABSTRACT: Lung contusion (LC) is an independent risk factor for acute respiratory distress syndrome. The final common pathway in ARDS involves accumulation of fluid in the alveoli. In this study, we demonstrate the application of a potential gene therapy approach by delivering the Na+/K+-ATPase pump subunits in a murine model of LC. We hypothesized that restoring the activity of the pump will result in removal of excess alveolar fluid and additionally reduce inflammation. Under anesthesia, C57/BL6 mice were struck along the right posterior axillary line 1 cm above the costal margin with a cortical contusion impactor. Immediately afterward, 100 μg of plasmid DNA coding for the α,β of the Na+/K+-ATPase pump were instilled into the lungs (LC-electroporation-pump group). Contusion only (LC-only) and a sham saline instillation group after contusion were used as controls (LC-electroporation-sham). By using a BTX 830 electroporator, eight electrical pulses of 200 V/cm field strength were applied transthoracically. Mice were killed at 24 hours, 48 hours, and 72 hours after delivery. Bronchial alveolar lavage was recollected to measure albumin and cytokines by enzyme-linked immunosorbent assay. Pulmonary compliance was measured, and lungs were subject to histopathologic analysis. After the electroporation and delivery of genes coding for the α,β subunits of the Na+/K+-ATPase pump, there was a significant mitigation of acute lung injury as evidenced by reduction in bronchial alveolar lavage levels of albumin, improved pressure volume curves, and reduced inflammation seen on histology. Electroporation-mediated gene transfer of the subunits of the Na+/K+-ATPase pump enhanced recovery from acute inflammatory lung injury after LC.
    The journal of trauma and acute care surgery. 01/2012; 72(1):32-9; discussion 39-40.
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    ABSTRACT: To examine the case mix and patient characteristics and outcomes of the nontrauma emergency (NTE) service in an academic Division of Acute Care Surgery. An NTE service (attending, chief resident, postgraduate year-3 and postgraduate year-2 residents, and two physician assistants) was created in July 2005 for all urgent and emergent inpatient and emergency department general surgery patient consults and admissions. An NTE database was created with prospective data collection of all NTE admissions initiated from November 1, 2007. Prospective data were collected by a dedicated trauma registrar and Acute Physiology and Chronic Health Evaluation-intensive care unit (ICU) coordinator daily. NTE case mix and ICU characteristics were reviewed for the 2-year time period January 1, 2008, through December 31, 2009. During the same time period, trauma operative cases and procedures were examined and compared with the NTE case mix. Thousand seven hundred eight patients were admitted to the NTE service during this time period (789 in 2008 and 910 in 2009). Surgical intervention was required in 70% of patients admitted to the NTE service. Exploratory laparotomy or laparoscopy was performed in 449 NTE patients, comprising 37% of all surgical procedures. In comparison, only 118 trauma patients (5.9% of admissions) required a major laparotomy or thoracotomy during the same time period. Acuity of illness of NTE patients was high, with a significant portion (13%) of NTE patients requiring ICU admission. NTE patients had higher admission Acute Physiology and Chronic Health Evaluation III scores [61.2 vs. 58.8 (2008); 58.2 vs. 55.8 (2009)], increased mortality [(9.71% vs. 4.89% (2008); 6.78% vs. 5.16% (2009)], and increased readmission rates (15.5% vs. 7.4%) compared with the total surgical ICU (SICU) admissions. In an era of declining operative caseload in trauma, the NTE service provides ample opportunity for complex general surgery decision making and operative procedures for surgical residency education, including advanced surgical critical care management. In addition, creation of an NTE service provides an optimal general surgery case mix, including major abdominal operations, that can augment declining trauma surgery caseloads, maintain acute care faculty surgical skills, and support general and acute care surgery residency training.
    The Journal of trauma 11/2011; 71(5):1422-6; discussion 1426-7. · 2.35 Impact Factor

Publication Stats

507 Citations
153.71 Total Impact Points

Institutions

  • 2013
    • Roswell Park Cancer Institute
      • Department of Medicine
      Buffalo, NY, United States
  • 2008–2013
    • University of Michigan
      • Department of Surgery
      Ann Arbor, Michigan, United States
  • 2012
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2003–2012
    • University at Buffalo, The State University of New York
      • • Department of Surgery
      • • Department of Biostatistics
      Buffalo, NY, United States
  • 2007–2008
    • State University of New York
      New York City, New York, United States
  • 2005
    • University of Rochester
      • Department of Pediatrics
      Rochester, New York, United States
  • 2002–2005
    • Erie County Medical Center
      United States