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1.
Am J Physiol Heart Circ Physiol ; 320(6): H2385-H2400, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33989079

RESUMEN

Cell-free hemoglobin (CFH) levels are elevated in septic shock and are higher in nonsurvivors. Whether CFH is only a marker of sepsis severity or is involved in pathogenesis is unknown. This study aimed to investigate whether CFH worsens sepsis-associated injuries and to determine potential mechanisms of harm. Fifty-one, 10-12 kg purpose-bred beagles were randomized to receive Staphylococcus aureus intrapulmonary challenges or saline followed by CFH infusions (oxyhemoglobin >80%) or placebo. Animals received antibiotics and intensive care support for 96 h. CFH significantly increased mean pulmonary arterial pressures and right ventricular afterload in both septic and nonseptic animals, effects that were significantly greater in nonsurvivors. These findings are consistent with CFH-associated nitric oxide (NO) scavenging and were associated with significantly depressed cardiac function, and worsened shock, lactate levels, metabolic acidosis, and multiorgan failure. In septic animals only, CFH administration significantly increased mean alveolar-arterial oxygenation gradients, also to a significantly greater degree in nonsurvivors. CFH-associated iron levels were significantly suppressed in infected animals, suggesting that bacterial iron uptake worsened pneumonia. Notably, cytokine levels were similar in survivors and nonsurvivors and were not predictive of outcome. In the absence and presence of infection, CFH infusions resulted in pulmonary hypertension, cardiogenic shock, and multiorgan failure, likely through NO scavenging. In the presence of infection alone, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism, and is a biologically plausible, nonantibiotic, noncytokine target for therapeutic intervention.NEW & NOTEWORTHY Cell-free hemoglobin (CFH) elevations are a known consequence of clinical sepsis. Using a two-by-two factorial design and extensive physiological and biochemical evidence, we found a direct mechanism of injury related to nitric oxide scavenging leading to pulmonary hypertension increasing right heart afterload, depressed cardiac function, worsening circulatory failure, and death, as well as an indirect mechanism related to iron toxicity. These discoveries alter conventional thinking about septic shock pathogenesis and provide novel therapeutic approaches.


Asunto(s)
Hemoglobinas/metabolismo , Neumonía/metabolismo , Arteria Pulmonar/fisiopatología , Choque Séptico/metabolismo , Infecciones Estafilocócicas/metabolismo , Acidosis/metabolismo , Acidosis/fisiopatología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/fisiopatología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Perros , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Hemoglobinas/farmacología , Hierro/metabolismo , Ácido Láctico/metabolismo , Insuficiencia Multiorgánica/metabolismo , Insuficiencia Multiorgánica/fisiopatología , Óxido Nítrico/metabolismo , Neumonía/fisiopatología , Intercambio Gaseoso Pulmonar , Distribución Aleatoria , Choque Séptico/fisiopatología , Staphylococcus aureus/crecimiento & desarrollo
2.
Rev Med Virol ; 31(6): e2228, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33694220

RESUMEN

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non-SARS-CoV2 infection supported the use of these agents in the present SARS-CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non-SARS-CoV2 viral infections do not support these agents' use for the SARS-CoV2 outbreak.


Asunto(s)
Fiebre Chikungunya/tratamiento farmacológico , Cloroquina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Mononucleosis Infecciosa/tratamiento farmacológico , Dengue Grave/tratamiento farmacológico , Verrugas/tratamiento farmacológico , Alphapapillomavirus/efectos de los fármacos , Alphapapillomavirus/inmunología , Alphapapillomavirus/patogenicidad , Antivirales/uso terapéutico , COVID-19/virología , Fiebre Chikungunya/inmunología , Fiebre Chikungunya/patología , Fiebre Chikungunya/virología , Virus Chikungunya/efectos de los fármacos , Virus Chikungunya/inmunología , Virus Chikungunya/patogenicidad , Virus del Dengue/efectos de los fármacos , Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , VIH/efectos de los fármacos , VIH/inmunología , VIH/patogenicidad , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Infecciones por VIH/virología , Hepacivirus/efectos de los fármacos , Hepacivirus/inmunología , Hepacivirus/patogenicidad , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/patología , Hepatitis C Crónica/virología , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/patogenicidad , Humanos , Mononucleosis Infecciosa/inmunología , Mononucleosis Infecciosa/patología , Mononucleosis Infecciosa/virología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Dengue Grave/inmunología , Dengue Grave/patología , Dengue Grave/virología , Resultado del Tratamiento , Verrugas/inmunología , Verrugas/patología , Verrugas/virología , Tratamiento Farmacológico de COVID-19
3.
Toxins (Basel) ; 13(1)2021 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-33450877

RESUMEN

Anti-toxin agents for severe B. anthracis infection will only be effective if they add to the benefit of the two mainstays of septic shock management, antibiotic therapy and titrated hemodynamic support. Both of these standard therapies could negate benefits related to anti-toxin treatment. At present, three anthrax anti-toxin antibody preparations have received US Food and Drug Administration (FDA) approval: Raxibacumab, Anthrax Immune Globulin Intravenous (AIGIV) and ETI-204. Each agent is directed at the protective antigen component of lethal and edema toxin. All three agents were compared to placebo in antibiotic-treated animal models of live B. anthracis infection, and Raxibacumab and AIGIV were compared to placebo when combined with standard hemodynamic support in a 96 h canine model of anthrax toxin-associated shock. However, only AIG has actually been administered to a group of infected patients, and this experience was not controlled and offers little insight into the efficacy of the agents. To provide a broader view of the potential effectiveness of these agents, this review examines the controlled preclinical experience either in antibiotic-treated B. anthracis models or in titrated hemodynamic-supported toxin-challenged canines. The strength and weaknesses of these preclinical experiences are discussed.


Asunto(s)
Carbunco/tratamiento farmacológico , Antibacterianos/uso terapéutico , Antígenos Bacterianos , Antitoxinas/uso terapéutico , Toxinas Bacterianas , Choque Séptico/terapia , Animales , Anticuerpos Monoclonales/uso terapéutico , Bacillus anthracis/efectos de los fármacos , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Hemodinámica , Humanos , Inmunoglobulinas Intravenosas , Estados Unidos , United States Food and Drug Administration
4.
Am J Physiol Heart Circ Physiol ; 320(1): H36-H51, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33064559

RESUMEN

Bacillus anthracis edema toxin (ET) inhibited lethal toxin-stimulated pulmonary artery pressure (Ppa) and increased lung cAMP levels in our previous study. We therefore examined whether ET inhibits hypoxic pulmonary vasoconstriction (HPV). Following baseline hypoxic measures in isolated perfused lungs from healthy rats, compared with diluent, ET perfusion reduced maximal Ppa increases (mean ± SE percentage of maximal Ppa increase with baseline hypoxia) during 6-min hypoxic periods (FIO2 = 0%) at 120 min (16 ± 6% vs. 51 ± 6%, P = 0.004) and 180 min (11.4% vs. 55 ± 6%, P = 0.01). Protective antigen-mAb (PA-mAb) and adefovir inhibit host cell edema factor uptake and cAMP production, respectively. In lungs perfused with ET following baseline measures, compared with placebo, PA-mAb treatment increased Ppa during hypoxia at 120 and 180 min (56 ± 6% vs. 10 ± 4% and 72 ± 12% vs. 12 ± 3%, respectively, P ≤ 0.01) as did adefovir (84 ± 10% vs. 16.8% and 123 ± 21% vs. 26 ± 11%, respectively, P ≤ 0.01). Compared with diluent, lung perfusion with ET for 180 min reduced the slope of the relationships between Ppa and increasing concentrations of endothelin-1 (ET-1) (21.12 ± 2.96 vs. 3.00 ± 0.76 × 108 cmH2O/M, P < 0.0001) and U46619, a thromboxane A2 analogue (7.15 ± 1.01 vs. 3.74 ± 0.31 × 107 cmH2O/M, P = 0.05) added to perfusate. In lungs isolated from rats after 15 h of in vivo infusions with either diluent, ET alone, or ET with PA-mAb, compared with diluent, the maximal Ppa during hypoxia and the slope of the relationship between change in Ppa and ET-1 concentration added to the perfusate were reduced in lungs from animals challenged with ET alone (P ≤ 0.004) but not with ET and PA-mAb together (P ≥ 0.73). Inhibition of HPV by ET could aggravate hypoxia during anthrax pulmonary infection.NEW & NOTEWORTHY The most important findings here are edema toxin's potent adenyl cyclase activity can interfere with hypoxic pulmonary vasoconstriction, an action that could worsen hypoxemia during invasive anthrax infection with lung involvement. These findings, coupled with other studies showing that lethal toxin can disrupt pulmonary vascular integrity, indicate that both toxins can contribute to pulmonary pathophysiology during infection. In combination, these investigations provide a further basis for the use of antitoxin therapies in patients with worsening invasive anthrax disease.


Asunto(s)
Antígenos Bacterianos/toxicidad , Presión Arterial/efectos de los fármacos , Toxinas Bacterianas/toxicidad , AMP Cíclico/metabolismo , Hipoxia/fisiopatología , Pulmón/irrigación sanguínea , Arteria Pulmonar/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Inhibidores de Adenilato Ciclasa/farmacología , Adenilil Ciclasas/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Modelos Animales de Enfermedad , Hipoxia/metabolismo , Masculino , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Ratas Sprague-Dawley , Sistemas de Mensajero Secundario , Regulación hacia Arriba , Vasoconstrictores/farmacología
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