Browsing by Subject "Acute lung injury"

Now showing 1 - 7 of 7
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    Acute Kidney Injury and Bronchopulmonary Dysplasia in Premature Neonates Born Less than 32 Weeks’ Gestation
    (Thieme, 2020-02) Starr, Michelle C.; Boohaker, Louis; Eldredge, Laurie C.; Menon, Shina; Griffin, Russell; Mayock, Dennis E.; Li, Linzi; Askenazi, David; Hingorani, Sangeeta; Pediatrics, School of Medicine
    Objective: This study aimed to evaluate the association between acute kidney injury (AKI) and bronchopulmonary dysplasia (BPD) in infants born <32 weeks of gestational age (GA). Study design: Present study is a secondary analysis of premature infants born at <32 weeks of GA in the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) retrospective cohort (n = 546). We stratified by gestational age and used logistic regression to determine association between AKI and moderate or severe BPD/mortality. Results: Moderate or severe BPD occurred in 214 of 546 (39%) infants, while death occurred in 32 of 546 (6%); the composite of moderate or severe BPD/death occurred in 246 of 546 (45%). For infants born ≤29 weeks of gestation, the adjusted odds ratio (OR) of AKI and the primary outcome was 1.15 (95% confidence interval [CI] = 0.47-2.86; p = 0.76). Infants born between 29 and 32 weeks of gestation with AKI had four-fold higher odds of moderate or severe BPD/death that remained after controlling for multiple factors (adjusted OR = 4.21, 95% CI: 2.07-8.61; p < 0.001). Conclusion: Neonates born between 29 and 32 weeks who develop AKI had a higher likelihood of moderate or severe BPD/death than those without AKI. Further studies are needed to validate our findings and evaluate mechanisms of multiorgan injury.
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    Acute Kidney Injury is Associated with Poor Lung Outcomes in Infants Born ≥32 Weeks of Gestational Age
    (Thieme, 2020-01) Starr, Michelle C.; Boohaker, Louis; Eldredge, Laurie C.; Menon, Shina; Griffin, Russell; Mayock, Dennis; Askenazi, David; Hingorani, Sangeeta; Pediatrics, School of Medicine
    Objective: This study aimed to evaluate the association between acute kidney injury (AKI) and lung outcomes in infants born ≥32 weeks of gestational age (GA). Study design: Secondary analysis of infants ≥32 weeks of GA in the assessment of worldwide acute kidney injury epidemiology in neonates (AWAKEN) retrospective cohort (n = 1,348). We used logistic regression to assess association between AKI and a composite outcome of chronic lung disease (CLD) or death at 28 days of age and linear regression to evaluate association between AKI and duration of respiratory support. Results: CLD occurred in 82/1,348 (6.1%) infants, while death occurred in 22/1,348 (1.6%); the composite of CLD/death occurred in 104/1,348 (7.7%). Infants with AKI had an almost five-fold increased odds of CLD/death, which remained after controlling for GA, maternal polyhydramnios, multiple gestations, 5-minute Apgar's score, intubation, and hypoxic-ischemic encephalopathy (adjusted odds ratio [OR] = 4.9, 95% confidence interval [CI]: 3.2-7.4; p < 0.0001). Infants with AKI required longer duration of respiratory support (count ratio = 1.59, 95% CI: 1.14-2.23, p = 0.003) and oxygen (count ratio = 1.43, 95% CI: 1.22-1.68, p < 0.0001) compared with those without AKI. Conclusion: AKI is associated with CLD/death and longer duration of respiratory support in infants born at ≥32 weeks of GA. Further prospective studies are needed to elucidate the pathophysiologic relationship.
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    Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody
    (European Respiratory Society, 2021-05-06) Quijada, Hector; Bermudez, Tadeo; Kempf, Carrie L.; Valera, Daniel G.; Garcia, Alexander N.; Camp, Sara M.; Song, Jin H.; Franco, Evelyn; Burt, Jessica K.; Sun, Belinda; Mascarenhas, Joseph B.; Burns, Kimberlie; Gaber, Amir; Oita, Radu C.; Reyes Hernon, Vivian; Barber, Christy; Moreno-Vinasco, Liliana; Sun, Xiaoguang; Cress, Anne E.; Martin, Diego; Liu, Zhonglin; Desai, Ankit A.; Natarajan, Viswanathan; Jacobson, Jeffrey R.; Dudek, Steven M.; Bime, Christian; Sammani, Saad; Garcia, Joe G.N.; Medicine, School of Medicine
    Rationale: The severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 pandemic has highlighted the serious unmet need for effective therapies that reduce acute respiratory distress syndrome (ARDS) mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor (TLR)4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target. Methods: Wild-type C57BL/6J or endothelial cell (EC)-cNAMPT -/- knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced ("one-hit") or a combined LPS/ventilator ("two-hit")-induced acute inflammatory lung injury model. A NAMPT-specific monoclonal antibody (mAb) imaging probe (99mTc-ProNamptor) was used to detect NAMPT expression in lung tissues. Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were used in vitro and in vivo. Results: Immunohistochemical, biochemical and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both pre-clinical ARDS models. Intravenous delivery of either eNAMPT-neutralising pAb or mAb significantly attenuated inflammatory lung injury (haematoxylin and eosin staining, bronchoalveolar lavage (BAL) protein, BAL polymorphonuclear cells, plasma interleukin-6) in both pre-clinical models. In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption. In vivo studies in wild-type and EC-cNAMPT -/- mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both pre-clinical ARDS models. Conclusions: These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway. In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine.
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    The Neglected Price of Pediatric Acute Kidney Injury: Non-renal Implications
    (Frontiers Media, 2022-06-30) Pande, Chetna K.; Smith, Mallory B.; Soranno, Danielle E.; Gist, Katja M.; Fuhrman, Dana Y.; Dolan, Kristin; Conroy, Andrea L.; Akcan-Arikan, Ayse; Pediatrics, School of Medicine
    Preclinical models and emerging translational data suggest that acute kidney injury (AKI) has far reaching effects on all other major organ systems in the body. Common in critically ill children and adults, AKI is independently associated with worse short and long term morbidity, as well as mortality, in these vulnerable populations. Evidence exists in adult populations regarding the impact AKI has on life course. Recently, non-renal organ effects of AKI have been highlighted in pediatric AKI survivors. Given the unique pediatric considerations related to somatic growth and neurodevelopmental consequences, pediatric AKI has the potential to fundamentally alter life course outcomes. In this article, we highlight the challenging and complex interplay between AKI and the brain, heart, lungs, immune system, growth, functional status, and longitudinal outcomes. Specifically, we discuss the biologic basis for how AKI may contribute to neurologic injury and neurodevelopment, cardiac dysfunction, acute lung injury, immunoparalysis and increased risk of infections, diminished somatic growth, worsened functional status and health related quality of life, and finally the impact on young adult health and life course outcomes.
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    Role of Covalent Modification of Hyaluronan with Inter-Alpha Inhibitor Heavy Chains During Acute Lung Injury
    (2019-04) Ni, Kevin Chen; Petrache, Irina; Evans-Molina, Carmella; Dong, X. Charlie; Goebl, Mark G.; Wek, Ronald C.
    The extracellular matrix (ECM) provides a structural and signaling platform for cells that comprise various organs, playing a critical role in tissue maintenance, injury, and repair. Hyaluronan (also known as hyaluronic acid, HA) is a ubiquitous ECM polysaccharide consisting of a repeating disaccharide backbone that can be covalently modified by the heavy chains (HC) of the serum protein inter-alpha-inhibitor (IαI) during inflammation. Known as the only covalent modification of HA, the HC linking of HA is exclusively mediated by the inflammation-induced secreted enzyme TNFα-stimulated gene-6 (TSG-6). Mice deficient for HC-HA formation, due to the lack of either TSG-6 or IαI, display reduced survival during systemic lipopolysaccharide (LPS)-induced endotoxic shock and its associated acute lung injury. We therefore hypothesized that HC-HA should play an important protective role against acute lung injury induced by intratracheal LPS or Pseudomonas aeruginosa (PA) gram-negative bacteria. We also identified that lung instillation of LPS or PA caused rapid induction of lung parenchymal HC-HA that was largely cleared during resolution of injury, indicative of a high rate of HA turnover and remodeling during reversible lung injury. However, using TSG-6 knockout mice, we determined that HC-HA exerted minimal protective effects against intratracheal LPS or PA-induced acute lung injury. To better address the differential roles of HC-HA during systemic versus localized intratracheal exposure to LPS, we characterized and compared the induction of HC-HA in plasma and lung in these two models. While lung parenchymal HC-HA formed in both injury models, intravascular HC-HA and TSG-6 were exclusively induced during systemic LPS exposure and were associated with improved outcomes, including decreased number of circulating neutrophils and plasma TNFα levels. Our results suggest that LPS induces HC-HA formation in various tissues depending on the route of exposure and that the specific intravascular induction of HCHA during systemic LPS exposure may have a protective role during endotoxic shock.
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    The Neglected Price of Pediatric Acute Kidney Injury: Non-renal Implications
    (Frontiers Media, 2022-06-30) Pande, Chetna K.; Smith, Mallory B.; Soranno, Danielle E.; Gist, Katja M.; Fuhrman, Dana Y.; Dolan, Kristin; Conroy, Andrea L.; Akcan-Arikan, Ayse; Pediatrics, School of Medicine
    Preclinical models and emerging translational data suggest that acute kidney injury (AKI) has far reaching effects on all other major organ systems in the body. Common in critically ill children and adults, AKI is independently associated with worse short and long term morbidity, as well as mortality, in these vulnerable populations. Evidence exists in adult populations regarding the impact AKI has on life course. Recently, non-renal organ effects of AKI have been highlighted in pediatric AKI survivors. Given the unique pediatric considerations related to somatic growth and neurodevelopmental consequences, pediatric AKI has the potential to fundamentally alter life course outcomes. In this article, we highlight the challenging and complex interplay between AKI and the brain, heart, lungs, immune system, growth, functional status, and longitudinal outcomes. Specifically, we discuss the biologic basis for how AKI may contribute to neurologic injury and neurodevelopment, cardiac dysfunction, acute lung injury, immunoparalysis and increased risk of infections, diminished somatic growth, worsened functional status and health related quality of life, and finally the impact on young adult health and life course outcomes.
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    Tissue alkaline phosphatase activity and expression in an experimental infant swine model of cardiopulmonary bypass with deep hypothermic circulatory arrest
    (BMC, 2020-08-12) Khailova, Ludmila; Robison, Justin; Jaggers, James; Ing, Richard; Lawson, Scott; Treece, Amy; Soranno, Danielle; Osorio Lujan, Suzanne; Davidson, Jesse A.; Pediatrics, School of Medicine
    Background: Infant cardiac surgery with cardiopulmonary bypass results in decreased circulating alkaline phosphatase that is associated with poor postoperative outcomes. Bovine intestinal alkaline phosphatase infusion represents a novel therapy for post-cardiac surgery organ injury. However, the effects of cardiopulmonary bypass and bovine-intestinal alkaline phosphatase infusion on tissue-level alkaline phosphatase activity/expression are unknown. Methods: Infant pigs (n = 20) underwent cardiopulmonary bypass with deep hypothermic circulatory arrest followed by four hours of intensive care. Seven control animals underwent mechanical ventilation only. Cardiopulmonary bypass/deep hypothermic circulatory arrest animals were given escalating doses of bovine intestinal alkaline phosphatase infusion (0-25 U/kg/hr.; n = 5/dose). Kidney, liver, ileum, jejunum, colon, heart and lung were collected for measurement of tissue alkaline phosphatase activity and mRNA. Results: Tissue alkaline phosphatase activity varied significantly across organs with the highest levels found in the kidney and small intestine. Cardiopulmonary bypass with deep hypothermic circulatory arrest resulted in decreased kidney alkaline phosphatase activity and increased lung alkaline phosphatase activity, with no significant changes in the other organs. Alkaline phosphatase mRNA expression was increased in both the lung and the ileum. The highest dose of bovine intestinal alkaline phosphatase resulted in increased kidney and liver tissue alkaline phosphatase activity. Conclusions: Changes in alkaline phosphatase activity after cardiopulmonary bypass with deep hypothermic circulatory arrest and bovine intestinal alkaline phosphatase delivery are tissue specific. Kidneys, lung, and ileal alkaline phosphatase appear most affected by cardiopulmonary bypass with deep hypothermic circulatory arrest and further research is warranted to determine the mechanism and biologic importance of these changes.