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Hong-Long Ji; Brant M. Wagener; Timothy J. Ness; Runzhen Zhao. Fibrinolytic or anti-plasmin (nafamostat) therapy for COVID-19: A timing challenge for clinicians. Pulmonary Pharmacology & Therapeutics 2021, 70, 102055 -102055.
AMA StyleHong-Long Ji, Brant M. Wagener, Timothy J. Ness, Runzhen Zhao. Fibrinolytic or anti-plasmin (nafamostat) therapy for COVID-19: A timing challenge for clinicians. Pulmonary Pharmacology & Therapeutics. 2021; 70 ():102055-102055.
Chicago/Turabian StyleHong-Long Ji; Brant M. Wagener; Timothy J. Ness; Runzhen Zhao. 2021. "Fibrinolytic or anti-plasmin (nafamostat) therapy for COVID-19: A timing challenge for clinicians." Pulmonary Pharmacology & Therapeutics 70, no. : 102055-102055.
Traumatic brain injury (TBI) is the leading cause of injury-related death and disability in patients under the age of 46 years. Survivors of the initial injury often endure systemic complications such as pulmonary infection and Pseudomonas aeruginosa is one of the most common causes of nosocomial pneumonia in intensive care units. Female patients are less likely to develop secondary pneumonia after TBI and preclinical studies have revealed a salutary role for estrogen after trauma. Therefore, we hypothesized that female mice would experience less mortality after post-TBI pneumonia with P. aeruginosa. We employed a mouse model of TBI followed by P. aeruginosa pneumonia. Male mice had greater mortality and impaired lung bacterial clearance after post-TBI pneumonia compared to female mice. This was confirmed as a difference in sex hormones as oophorectomized wild-type mice had mortality and lung bacterial clearance similar to male mice. There were differences in tumor necrosis factor-α secretion in male and female alveolar macrophages after P. aeruginosa infection. Finally, injection of male or oophorectomized wild-type female mice with estrogen restored lung bacterial clearance and prevented mortality. Our model of TBI followed by P. aeruginosa pneumonia is among the first to reveal sex dimorphism in secondary, long-term TBI complications.
Jean-Francois Pittet; Parker J. Hu; Jaideep Honavar; Angela P. Brandon; Cilina A. Evans; Ms. Rebekah Muthalaly; Qiang Ding; Brant M. Wagener. Estrogen Alleviates Sex-Dependent Differences in Lung Bacterial Clearance and Mortality Secondary to Bacterial Pneumonia after Traumatic Brain Injury. Journal of Neurotrauma 2020, 1 .
AMA StyleJean-Francois Pittet, Parker J. Hu, Jaideep Honavar, Angela P. Brandon, Cilina A. Evans, Ms. Rebekah Muthalaly, Qiang Ding, Brant M. Wagener. Estrogen Alleviates Sex-Dependent Differences in Lung Bacterial Clearance and Mortality Secondary to Bacterial Pneumonia after Traumatic Brain Injury. Journal of Neurotrauma. 2020; ():1.
Chicago/Turabian StyleJean-Francois Pittet; Parker J. Hu; Jaideep Honavar; Angela P. Brandon; Cilina A. Evans; Ms. Rebekah Muthalaly; Qiang Ding; Brant M. Wagener. 2020. "Estrogen Alleviates Sex-Dependent Differences in Lung Bacterial Clearance and Mortality Secondary to Bacterial Pneumonia after Traumatic Brain Injury." Journal of Neurotrauma , no. : 1.
The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly reached pandemic proportions, and knowledge about this virus and coronavirus disease 2019 (COVID-19) has expanded rapidly. This review focuses primarily on mechanisms that contribute to acute cardiac injury and dysfunction, which are common in patients with severe disease. The etiology of cardiac injury is multifactorial, and the extent is likely enhanced by preexisting cardiovascular disease. Disruption of homeostatic mechanisms secondary to pulmonary pathology ranks high on the list, and there is growing evidence that direct infection of cardiac cells can occur. Angiotensin-converting enzyme 2 (ACE2) plays a central role in COVID-19 and is a necessary receptor for viral entry into human cells. ACE2 normally not only eliminates angiotensin II (Ang II) by converting it to Ang-(1–7) but also elicits a beneficial response profile counteracting that of Ang II. Molecular analyses of single nuclei from human hearts have shown that ACE2 is most highly expressed by pericytes. Given the important roles that pericytes have in the microvasculature, infection of these cells could compromise myocardial supply to meet metabolic demand. Furthermore, ACE2 activity is crucial for opposing adverse effects of locally generated Ang II, so virus-mediated internalization of ACE2 could exacerbate pathology by this mechanism. While the role of cardiac pericytes in acute heart injury by SARS-CoV-2 requires investigation, expression of ACE2 by these cells has broader implications for cardiac pathophysiology.
Fulton A. Robinson; Ryan. P. Mihealsick; Brant M. Wagener; Peter Hanna; Megan D. Poston; Igor R. Efimov; Kalyanam Shivkumar; Donald B. Hoover. Role of angiotensin-converting enzyme 2 and pericytes in cardiac complications of COVID-19 infection. American Journal of Physiology-Heart and Circulatory Physiology 2020, 319, H1059 -H1068.
AMA StyleFulton A. Robinson, Ryan. P. Mihealsick, Brant M. Wagener, Peter Hanna, Megan D. Poston, Igor R. Efimov, Kalyanam Shivkumar, Donald B. Hoover. Role of angiotensin-converting enzyme 2 and pericytes in cardiac complications of COVID-19 infection. American Journal of Physiology-Heart and Circulatory Physiology. 2020; 319 (5):H1059-H1068.
Chicago/Turabian StyleFulton A. Robinson; Ryan. P. Mihealsick; Brant M. Wagener; Peter Hanna; Megan D. Poston; Igor R. Efimov; Kalyanam Shivkumar; Donald B. Hoover. 2020. "Role of angiotensin-converting enzyme 2 and pericytes in cardiac complications of COVID-19 infection." American Journal of Physiology-Heart and Circulatory Physiology 319, no. 5: H1059-H1068.
Pseudomonas aeruginosa is a lethal pathogen that causes high mortality and morbidity in immunocompromised and critically ill patients. The Type III secretion system (T3SS) of P. aeruginosa mediates many of the adverse effects of infection with this pathogen including increased lung permeability in a toll-like receptor 4/Rho A/plasminogen activator inhibitor (PAI)-1-dependent manner. Alpha-tocopherol has anti-inflammatory properties that may make it a useful adjunct in treatment of this moribund infection. We measured transendothelial and transepithelial resistance, Rho A and PAI-1 activation, stress fiber formation, P. aeruginosa T3SS exoenzyme (Exo Y) intoxication into host cells, and survival in a murine model of pneumonia in the presence of P. aeruginosa and pretreatment with α-tocopherol. We found that α-tocopherol alleviated P. aeruginosa-mediated alveolar endothelial and epithelial paracellular permeability by inhibiting RhoA, in part, via PAI-1 activation and increased survival in a mouse model of P. aeruginosa pneumonia. Furthermore, we found that α-tocopherol decreased the activation of RhoA and PAI-1 by blocking the injection of T3SS exoenzymes into alveolar epithelial cells. P. aeruginosa is becoming increasingly antibiotic-resistant. We provide evidence that α-tocopherol could be a useful therapeutic agent for individuals that are susceptible to infection with P. aeruginosa such as those who are immunocompromised or critically ill.
Brant M. Wagener; Naseem Anjum; Cilina Evans; Angela Brandon; Jaideep Honavar; Judy Creighton; Maret Traber; Robert L. Stuart; Troy Stevens; Jean-Francois Pittet. α-Tocopherol Attenuates the Severity ofPseudomonas aeruginosa–induced Pneumonia. American Journal of Respiratory Cell and Molecular Biology 2020, 63, 234 -243.
AMA StyleBrant M. Wagener, Naseem Anjum, Cilina Evans, Angela Brandon, Jaideep Honavar, Judy Creighton, Maret Traber, Robert L. Stuart, Troy Stevens, Jean-Francois Pittet. α-Tocopherol Attenuates the Severity ofPseudomonas aeruginosa–induced Pneumonia. American Journal of Respiratory Cell and Molecular Biology. 2020; 63 (2):234-243.
Chicago/Turabian StyleBrant M. Wagener; Naseem Anjum; Cilina Evans; Angela Brandon; Jaideep Honavar; Judy Creighton; Maret Traber; Robert L. Stuart; Troy Stevens; Jean-Francois Pittet. 2020. "α-Tocopherol Attenuates the Severity ofPseudomonas aeruginosa–induced Pneumonia." American Journal of Respiratory Cell and Molecular Biology 63, no. 2: 234-243.
Andrew B. Barker; Brant M. Wagener. An Ounce of Prevention May Prevent Hospitalization. Physiological Reviews 2020, 100, 1347 -1348.
AMA StyleAndrew B. Barker, Brant M. Wagener. An Ounce of Prevention May Prevent Hospitalization. Physiological Reviews. 2020; 100 (3):1347-1348.
Chicago/Turabian StyleAndrew B. Barker; Brant M. Wagener. 2020. "An Ounce of Prevention May Prevent Hospitalization." Physiological Reviews 100, no. 3: 1347-1348.
Pseudomonas aeruginosa is an opportunistic pathogen that causes pneumonia in immunocompromised and intensive care unit (ICU) patients. During host infection, P. aeruginosa upregulates the type III secretion system (T3SS), which is used to intoxicate host cells with exoenzyme (Exo) virulence factors. Of the four known Exo virulence factors (U, S, T and Y), ExoU has been shown in prior studies to associate with high mortality rates. Preclinical studies have shown that ExoY is an important edema factor in lung infection caused by P. aeruginosa, although its importance in clinical isolates of P. aeruginosa is unknown. We hypothesized that expression of ExoY would be highly prevalent in clinical isolates and would significantly contribute to patient morbidity secondary to P. aeruginosa pneumonia. A single-center, prospective observational study was conducted at the University of Alabama at Birmingham Hospital. Mechanically ventilated ICU patients with a bronchoalveolar lavage fluid culture positive for P. aeruginosa were included. Enrolled patients were followed from ICU admission to discharge and clinical P. aeruginosa isolates were genotyped for the presence of exoenzyme genes. Ninety-nine patients were enrolled in the study. ExoY was present in 93% of P. aeruginosa clinical isolates. Moreover, ExoY alone (ExoY+/ExoU−) was present in 75% of P. aeruginosa isolates, compared to 2% ExoU alone (ExoY−/ExoU+). We found that bacteria isolated from human samples expressed active ExoY and ExoU, and the presence of ExoY in clinical isolates was associated with end-organ dysfunction. This is the first study we are aware of that demonstrates that ExoY is important in clinical outcomes secondary to nosocomial pneumonia.
Brant M. Wagener; Naseem Anjum; Sarah C. Christiaans; Morgan E. Banks; Jordan C. Parker; Adam T. Threet; Rashidra R. Walker; Kayla D. Isbell; Stephen A. Moser; Troy Stevens; Mikhail F. Alexeyev; Jonathon P. Audia; Wito Richter; Kierra S. Hardy; Lina Abou Saleh; Charity Morgan; Jean-François Pittet. Exoenzyme Y Contributes to End-Organ Dysfunction Caused by Pseudomonas aeruginosa Pneumonia in Critically Ill Patients: An Exploratory Study. Toxins 2020, 12, 369 .
AMA StyleBrant M. Wagener, Naseem Anjum, Sarah C. Christiaans, Morgan E. Banks, Jordan C. Parker, Adam T. Threet, Rashidra R. Walker, Kayla D. Isbell, Stephen A. Moser, Troy Stevens, Mikhail F. Alexeyev, Jonathon P. Audia, Wito Richter, Kierra S. Hardy, Lina Abou Saleh, Charity Morgan, Jean-François Pittet. Exoenzyme Y Contributes to End-Organ Dysfunction Caused by Pseudomonas aeruginosa Pneumonia in Critically Ill Patients: An Exploratory Study. Toxins. 2020; 12 (6):369.
Chicago/Turabian StyleBrant M. Wagener; Naseem Anjum; Sarah C. Christiaans; Morgan E. Banks; Jordan C. Parker; Adam T. Threet; Rashidra R. Walker; Kayla D. Isbell; Stephen A. Moser; Troy Stevens; Mikhail F. Alexeyev; Jonathon P. Audia; Wito Richter; Kierra S. Hardy; Lina Abou Saleh; Charity Morgan; Jean-François Pittet. 2020. "Exoenzyme Y Contributes to End-Organ Dysfunction Caused by Pseudomonas aeruginosa Pneumonia in Critically Ill Patients: An Exploratory Study." Toxins 12, no. 6: 369.
Mike T. Lin; Ron Balczon; Jean-Francois Pittet; Brant M. Wagener; Stephen A. Moser; K. Adam Morrow; Sarah Voth; C. Michael Francis; Silas Leavesley; Jessica Bell; Diego F. Alvarez; Troy Stevens. Nosocomial Pneumonia Elicits an Endothelial Proteinopathy: Evidence for a Source of Neurotoxic Amyloids in Critically Ill Patients. American Journal of Respiratory and Critical Care Medicine 2018, 198, 1575 -1578.
AMA StyleMike T. Lin, Ron Balczon, Jean-Francois Pittet, Brant M. Wagener, Stephen A. Moser, K. Adam Morrow, Sarah Voth, C. Michael Francis, Silas Leavesley, Jessica Bell, Diego F. Alvarez, Troy Stevens. Nosocomial Pneumonia Elicits an Endothelial Proteinopathy: Evidence for a Source of Neurotoxic Amyloids in Critically Ill Patients. American Journal of Respiratory and Critical Care Medicine. 2018; 198 (12):1575-1578.
Chicago/Turabian StyleMike T. Lin; Ron Balczon; Jean-Francois Pittet; Brant M. Wagener; Stephen A. Moser; K. Adam Morrow; Sarah Voth; C. Michael Francis; Silas Leavesley; Jessica Bell; Diego F. Alvarez; Troy Stevens. 2018. "Nosocomial Pneumonia Elicits an Endothelial Proteinopathy: Evidence for a Source of Neurotoxic Amyloids in Critically Ill Patients." American Journal of Respiratory and Critical Care Medicine 198, no. 12: 1575-1578.
Trauma is the leading cause of death and disability in patients aged 1–46 y. Severely injured patients experience considerable blood loss and hemorrhagic shock requiring treatment with massive transfusion of red blood cells (RBCs). Preclinical and retrospective human studies in trauma patients have suggested that poorer therapeutic efficacy, increased severity of organ injury, and increased bacterial infection are associated with transfusion of large volumes of stored RBCs, although the mechanisms are not fully understood. We developed a murine model of trauma hemorrhage (TH) followed by resuscitation with plasma and leukoreduced RBCs (in a 1:1 ratio) that were banked for 0 (fresh) or 14 (stored) days. Two days later, lungs were infected with Pseudomonas aeruginosa K-strain (PAK). Resuscitation with stored RBCs significantly increased the severity of lung injury caused by P. aeruginosa, as demonstrated by higher mortality (median survival 35 h for fresh RBC group and 8 h for stored RBC group; p < 0.001), increased pulmonary edema (mean [95% CI] 106.4 μl [88.5–124.3] for fresh RBCs and 192.5 μl [140.9–244.0] for stored RBCs; p = 0.003), and higher bacterial numbers in the lung (mean [95% CI] 1.2 × 107 [−1.0 × 107 to 2.5 × 107] for fresh RBCs and 3.6 × 107 [2.5 × 107 to 4.7 × 107] for stored RBCs; p = 0.014). The mechanism underlying this increased infection susceptibility and severity was free-heme-dependent, as recombinant hemopexin or pharmacological inhibition or genetic deletion of toll-like receptor 4 (TLR4) during TH and resuscitation completely prevented P. aeruginosa–induced mortality after stored RBC transfusion (p < 0.001 for all groups relative to stored RBC group). Evidence from studies transfusing fresh and stored RBCs mixed with stored and fresh RBC supernatants, respectively, indicated that heme arising both during storage and from RBC hemolysis post-resuscitation plays a role in increased mortality after PAK (p < 0.001). Heme also increased endothelial permeability and inhibited macrophage-dependent phagocytosis in cultured cells. Stored RBCs also increased circulating high mobility group box 1 (HMGB1; mean [95% CI] 15.4 ng/ml [6.7–24.0] for fresh RBCs and 50.3 ng/ml [12.3–88.2] for stored RBCs), and anti-HMGB1 blocking antibody protected against PAK-induced mortality in vivo (p = 0.001) and restored macrophage-dependent phagocytosis of P. aeruginosa in vitro. Finally, we showed that TH patients, admitted to the University of Alabama at Birmingham ER between 1 January 2015 and 30 April 2016 (n = 50), received high micromolar–millimolar levels of heme proportional to the number of units transfused, sufficient to overwhelm endogenous hemopexin levels early after TH and resuscitation. Limitations of the study include lack of assessment of temporal changes in different products of hemolysis after resuscitation and the small sample size precluding testing of associations between heme levels and adverse outcomes in resuscitated TH patients. We provide evidence that large volume resuscitation with stored blood, compared to fresh blood, in mice increases mortality from subsequent pneumonia, which occurs via mechanisms sensitive to hemopexin and TLR4 and HMGB1 inhibition.
Brant M. Wagener; Parker J. Hu; Joo-Yeun Oh; Cilina A. Evans; Jillian R. Richter; Jaideep Honavar; Angela P. Brandon; Judy Creighton; Shannon W. Stephens; Charity Morgan; Randal O. Dull; Marisa B. Marques; Jeffrey D. Kerby; Jean-Francois Pittet; Rakesh P. Patel. Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study. PLOS Medicine 2018, 15, e1002522 .
AMA StyleBrant M. Wagener, Parker J. Hu, Joo-Yeun Oh, Cilina A. Evans, Jillian R. Richter, Jaideep Honavar, Angela P. Brandon, Judy Creighton, Shannon W. Stephens, Charity Morgan, Randal O. Dull, Marisa B. Marques, Jeffrey D. Kerby, Jean-Francois Pittet, Rakesh P. Patel. Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study. PLOS Medicine. 2018; 15 (3):e1002522.
Chicago/Turabian StyleBrant M. Wagener; Parker J. Hu; Joo-Yeun Oh; Cilina A. Evans; Jillian R. Richter; Jaideep Honavar; Angela P. Brandon; Judy Creighton; Shannon W. Stephens; Charity Morgan; Randal O. Dull; Marisa B. Marques; Jeffrey D. Kerby; Jean-Francois Pittet; Rakesh P. Patel. 2018. "Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study." PLOS Medicine 15, no. 3: e1002522.
The release of damage-associated molecular pattern molecules (DAMPs) in the extracellular space secondary to injury has been shown to cause systemic activation of the coagulation system and endothelial cell damage. We hypothesized that pediatric trauma patients with increased levels of histone-complexed DNA fragments (hcDNA) would have evidence of coagulopathy and endothelial damage that would be associated with poor outcomes. We conducted a prospective observational study of 149 pediatric trauma patients and 62 control patients at two level 1 pediatric trauma centers from 2013–2016. Blood samples were collected upon arrival and at 24 hours, analyzed for hcDNA, coagulation abnormalities, endothelial damage, and clinical outcome. Platelet aggregation was assessed with impedance aggregometry (Multiplate®) and coagulation parameters were assessed by measuring PT ratio in plasma and the use of viscoelastic techniques (ROTEM®) in whole blood. The median age was 8.3 years, the median injury severity score (ISS) was 20, and overall mortality was 10%. Significantly higher levels of hcDNA were found on admission in patients with severe injury (ISS > 25), coagulopathy, and/or abnormal platelet aggregation. Patients with high hcDNA levels also had significant elevations in plasma levels of syndecan-1, suggesting damage to the endothelial glycocalyx. Finally, significantly higher hcDNA levels were found in non-survivors. hcDNA is released following injury and correlates with coagulopathy, endothelial glycocalyx damage, and poor clinical outcome early after severe pediatric trauma. These results indicate that hcDNA may play an important role in development of coagulation abnormalities and endothelial glycocalyx damage in children following trauma.
Robert Russell; Sarah C. Christiaans; Tate R. Nice; Morgan Banks; Vincent E. Mortellaro; Charity J Morgan; Amy Duhachek-Stapelman; Steven J. Lisco; Jeffrey D. Kerby; Brant M. Wagener; Mike K. Chen; Jean-François Pittet. Histone-Complexed DNA Fragments Levels are Associated with Coagulopathy, Endothelial Cell Damage, and Increased Mortality after Severe Pediatric Trauma. Shock 2018, 49, 44 -52.
AMA StyleRobert Russell, Sarah C. Christiaans, Tate R. Nice, Morgan Banks, Vincent E. Mortellaro, Charity J Morgan, Amy Duhachek-Stapelman, Steven J. Lisco, Jeffrey D. Kerby, Brant M. Wagener, Mike K. Chen, Jean-François Pittet. Histone-Complexed DNA Fragments Levels are Associated with Coagulopathy, Endothelial Cell Damage, and Increased Mortality after Severe Pediatric Trauma. Shock. 2018; 49 (1):44-52.
Chicago/Turabian StyleRobert Russell; Sarah C. Christiaans; Tate R. Nice; Morgan Banks; Vincent E. Mortellaro; Charity J Morgan; Amy Duhachek-Stapelman; Steven J. Lisco; Jeffrey D. Kerby; Brant M. Wagener; Mike K. Chen; Jean-François Pittet. 2018. "Histone-Complexed DNA Fragments Levels are Associated with Coagulopathy, Endothelial Cell Damage, and Increased Mortality after Severe Pediatric Trauma." Shock 49, no. 1: 44-52.
Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Even when patients survive the initial insult, there is significant morbidity and mortality secondary to subsequent pulmonary edema, acute lung injury (ALI), and nosocomial pneumonia. Whereas the relationship between TBI and secondary pulmonary complications is recognized, little is known about the mechanistic interplay of the two phenomena. Changes in mental status secondary to acute brain injury certainly impair airway- and lung-protective mechanisms. However, clinical and translational evidence suggests that more specific neuronal and cellular mechanisms contribute to impaired systemic and lung immunity that increases the risk of TBI-mediated lung injury and infection. To better understand the cellular mechanisms of that immune impairment, we review here the current clinical data that support TBI-induced impairment of systemic and lung immunity. Furthermore, we also review the animal models that attempt to reproduce human TBI. Additionally, we examine the possible role of damage-associated molecular patterns, the chlolinergic anti-inflammatory pathway, and sex dimorphism in post-TBI ALI. In the last part of the review, we discuss current treatments and future pharmacological therapies, including fever control, tracheostomy, and corticosteroids, aimed to prevent and treat pulmonary edema, ALI, and nosocomial pneumonia after TBI.
Parker J. Hu; Jean-Francois Pittet; Jeffrey D. Kerby; Patrick L. Bosarge; Brant M. Wagener. Acute brain trauma, lung injury, and pneumonia: more than just altered mental status and decreased airway protection. American Journal of Physiology-Lung Cellular and Molecular Physiology 2017, 313, L1 -L15.
AMA StyleParker J. Hu, Jean-Francois Pittet, Jeffrey D. Kerby, Patrick L. Bosarge, Brant M. Wagener. Acute brain trauma, lung injury, and pneumonia: more than just altered mental status and decreased airway protection. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2017; 313 (1):L1-L15.
Chicago/Turabian StyleParker J. Hu; Jean-Francois Pittet; Jeffrey D. Kerby; Patrick L. Bosarge; Brant M. Wagener. 2017. "Acute brain trauma, lung injury, and pneumonia: more than just altered mental status and decreased airway protection." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 1: L1-L15.
Parker J. Hu; Rindi Uhlich; Jeff Kerby; Brant M. Wagener; Jean-Francois Pittet; Patrick L. Bosarge. Splenectomy Does Not Affect the Development of Ventilator Associated Pneumonia Following Severe Traumatic Brain Injury. Journal of the American College of Surgeons 2016, 223, e206 -e207.
AMA StyleParker J. Hu, Rindi Uhlich, Jeff Kerby, Brant M. Wagener, Jean-Francois Pittet, Patrick L. Bosarge. Splenectomy Does Not Affect the Development of Ventilator Associated Pneumonia Following Severe Traumatic Brain Injury. Journal of the American College of Surgeons. 2016; 223 (4):e206-e207.
Chicago/Turabian StyleParker J. Hu; Rindi Uhlich; Jeff Kerby; Brant M. Wagener; Jean-Francois Pittet; Patrick L. Bosarge. 2016. "Splenectomy Does Not Affect the Development of Ventilator Associated Pneumonia Following Severe Traumatic Brain Injury." Journal of the American College of Surgeons 223, no. 4: e206-e207.
Background: Patients with acute respiratory distress syndrome who retain maximal alveolar fluid clearance (AFC) have better clinical outcomes. The release of endogenous catecholamines associated with shock or the administration of β2-adrenergic receptor (β2AR) agonists enhances AFC via a 3′-5′-cyclic adenosine monophosphate–dependent mechanism. The authors have previously reported that transforming growth factor-β1 (TGF-β1) and interleukin-8 (IL-8), two major mediators of alveolar inflammation associated with the early phase of acute respiratory distress syndrome, inhibit AFC upregulation by β2AR agonists via a phosphoinositol-3-kinase (PI3K)–dependent mechanism. However, whether TGF-β1 and IL-8 cause an additive or synergistic inhibition of AFC is unclear. Thus, the central hypothesis of the study was to determine whether they synergistically inhibit the β2AR-stimulated AFC by activating two different isoforms of PI3K. Methods: The effects of TGF-β1 or IL-8 on β2AR agonist–stimulated net alveolar fluid transport were studied using short-circuit current studies. Molecular pathways of inhibition were confirmed by pharmacologic inhibitors and Western blotting of p-Akt, G-protein–coupled receptor kinase 2, protein kinase C-ζ, and phospho-β2AR. Finally, our observations were confirmed by an in vivo model of AFC. Results: Combined exposure to TGF-β1 and IL-8/cytokine-induced neutrophil chemoattractant-1 caused synergistic inhibition of β2AR agonist–stimulated vectorial Cl− across alveolar epithelial type II cells (n = 12 in each group). This effect was explained by activation of different isoforms of PI3K by TGF-β1 and IL-8/cytokine-induced neutrophil chemoattractant-1 (n = 12 in each group). Furthermore, the inhibitory effect of TGF-β1 on 3′-5′-cyclic adenosine monophosphate–stimulated alveolar epithelial fluid transport required the presence of IL-8/cytokine-induced neutrophil chemoattractant-1 (n = 12 in each group). Inhibition of cytokine-induced neutrophil chemoattractant-1 prevented TGF-β1–mediated heterologous β2AR downregulation and restored physiologic β2AR agonist–stimulated AFC in rats (n = 6 in each group). Conclusions: TGF-β1 and IL-8 have a synergistic inhibitory effect on β2AR-mediated stimulation of pulmonary edema removal by the alveolar epithelium. This result may, in part, explain why a large proportion of the patients with acute respiratory distress syndrome have impaired AFC.
Brant M. Wagener; Jérémie Roux; Michel Carles; Jean-Francois Pittet. Synergistic Inhibition of β2-adrenergic Receptor–mediated Alveolar Epithelial Fluid Transport by Interleukin-8 and Transforming Growth Factor-β. Anesthesiology 2015, 122, 1084 -1092.
AMA StyleBrant M. Wagener, Jérémie Roux, Michel Carles, Jean-Francois Pittet. Synergistic Inhibition of β2-adrenergic Receptor–mediated Alveolar Epithelial Fluid Transport by Interleukin-8 and Transforming Growth Factor-β. Anesthesiology. 2015; 122 (5):1084-1092.
Chicago/Turabian StyleBrant M. Wagener; Jérémie Roux; Michel Carles; Jean-Francois Pittet. 2015. "Synergistic Inhibition of β2-adrenergic Receptor–mediated Alveolar Epithelial Fluid Transport by Interleukin-8 and Transforming Growth Factor-β." Anesthesiology 122, no. 5: 1084-1092.