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Recombinant human DNase-I improves acute respiratory distress syndrome via neutrophil extracellular trap degradation.
Jarrahi, Abbas; Khodadadi, Hesam; Moore, Nicholas S; Lu, Yujiao; Awad, Mohamed E; Salles, Evila L; Vaibhav, Kumar; Baban, Babak; Dhandapani, Krishnan M.
  • Jarrahi A; Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Khodadadi H; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Moore NS; Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Lu Y; Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Awad ME; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Salles EL; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Vaibhav K; Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Baban B; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, Georgia, USA; Department of Surgery, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
  • Dhandapani KM; Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, Georgia, USA. Electronic address: kdhandapani@augusta.edu.
J Thromb Haemost ; 2023 May 16.
Article in English | MEDLINE | ID: covidwho-20237345
ABSTRACT

BACKGROUND:

Respiratory failure is the primary cause of death in patients with COVID-19, whereas coagulopathy is associated with excessive inflammation and multiorgan failure. Neutrophil extracellular traps (NETs) may exacerbate inflammation and provide a scaffold for thrombus formation.

OBJECTIVES:

The goal of this study was to determine whether degradation of NETs by recombinant human DNase-I (rhDNase), a safe, Food and Drug Administration-approved drug, reduces excessive inflammation, reverses aberrant coagulation, and improves pulmonary perfusion after experimental acute respiratory distress syndrome (ARDS).

METHODS:

Intranasal poly(IC), a synthetic double-stranded RNA, was administered to adult mice for 3 consecutive days to simulate a viral infection, and these subjects were randomized to treatment arms, which received either an intravenous placebo or rhDNase. The effects of rhDNase on immune activation, platelet aggregation, and coagulation were assessed in mice and donor human blood.

RESULTS:

NETs were observed in bronchoalveolar lavage fluid and within regions of hypoxic lung tissue after experimental ARDS. The administration of rhDNase mitigated peribronchiolar, perivascular, and interstitial inflammation induced by poly(IC). In parallel, rhDNase degraded NETs, attenuated platelet-NET aggregates, reduced platelet activation, and normalized the clotting time to improve regional perfusion, as observed using gross morphology, histology, and microcomputed tomographic imaging in mice. Similarly, rhDNase reduced NETs and attenuated platelet activation in human blood.

CONCLUSION:

NETs exacerbate inflammation and promote aberrant coagulation by providing a scaffold for aggregated platelets after experimental ARDS. Intravenous administration of rhDNase degrades NETs and attenuates coagulopathy in ARDS, providing a promising translational approach to improve pulmonary structure and function after ARDS.
Keywords

Full text: Available Collection: International databases Database: MEDLINE Type of study: Experimental Studies / Randomized controlled trials Language: English Journal subject: Hematology Year: 2023 Document Type: Article Affiliation country: J.jtha.2023.04.044

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Experimental Studies / Randomized controlled trials Language: English Journal subject: Hematology Year: 2023 Document Type: Article Affiliation country: J.jtha.2023.04.044