Scripties UMCG - Rijksuniversiteit Groningen
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Combination therapy of antithrombin and alpha-1 proteinase inhibitor in a murine model of direct acute lung injury.

(2017) Juschten, J. (Jenny)

Acute respiratory distress syndrome (ARDS) is characterized by hypoxemic respiratory failure following an either direct (e.g. pneumonia) or indirect (e.g. sepsis) pulmonary insult. Dealing with hypoxemia remains the major challenge at bedside and is currently approached with lung-protective mechanical ventilation since specific treatment targeting the pathogenesis of ARDS is lacking.
Pathological hallmarks of ARDS are uncontrolled inflammation and coagulation leading to alveolar and interstitial edema, as well as infiltration of inflammatory cells in the alveolar space. Various cytokines, proteases and their inhibitors play a pivotal role in modulation of inflammation. Recent evidence suggests that proteinase inhibitors antithrombin (AT) and α1-protease-inhibitor (A1PI), may exert anti-inflammatory, anti-coagulant and immunomodulatory properties and may even have synergistic beneficial effect in diminishing inflammation. We hypothesize that combination therapy of AT and A1PI (COMBO therapy) has beneficial effect on lung damage and inflammatory markers in a murine model of direct acute lung injury.
Balb/c mice (n=44) received 5 mg/kg LPS (E. Coli, 0127:B8) intranasally (i.n.) simulating direct acute lung injury (T=0). One hour later (T=1) the intervention drugs AT, A1PI only and COMBO therapy were administered intraperitoneally (i.p.) and at T=6 all mice were sacrificed. State of inflammation was determined using Luminex to quantify levels of inflammatory markers TNFα, IL-1β, IL-6, KC and IL-10 in plasma and bronchoalveolar fluid (BALF), and assessing total protein levels and neutrophil influx in BALF.
Intranasal LPS administration induced lung injury, evidenced by markedly increased levels of TNF-α and IL-1β in BALF and increased vascular permeability in all intervention groups and the control group compared to the vehicle group (P<0.05, for all groups compared to vehicle).
This study did not detect any differences with regards to markers of inflammation, neutrophil migration or alveolar-capillary permeability between the intervention groups compared to the control group.
This study investigated the combination therapy of AT and A1PI in a murine model of direct ARDS. No differences in markers of inflammation, neutrophil migration or alveolar-capillary permeability were detected between the intervention groups and the saline control group, not showing a beneficial effect of COMBO therapy. Future experiments are needed to test COMBO in different models, including pretreatment and an indirect lung injury model, to draw firm conclusions regarding the efficacy of COMBO.

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