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Inhibition of TNF Receptor p55 By a Domain Antibody Attenuates the Initial Phase of Acid-Induced Lung Injury in Mice

View Article: PubMed Central - PubMed

ABSTRACT

Background: Tumor necrosis factor-α (TNF) is strongly implicated in the development of acute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has been hampered by its complex biology. TNF signals through two receptors, p55 and p75, which play differential roles in pulmonary edema formation during ARDS. We have recently shown that inhibition of p55 by a novel domain antibody (dAb™) attenuated ventilator-induced lung injury. In the current study, we explored the efficacy of this antibody in mouse models of acid-induced lung injury to investigate the longer consequences of treatment.

Methods: We employed two acid-induced injury models, an acute ventilated model and a resolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally or intranasally with p55-targeting dAb or non-targeting “dummy” dAb, 1 or 4 h before acid instillation.

Results: Acid instillation in the dummy dAb group caused hypoxemia, increased respiratory system elastance, pulmonary inflammation, and edema in both the ventilated and resolving models. Pretreatment with p55-targeting dAb significantly attenuated physiological markers of ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in the ventilated model, with signs that altered cytokine production and leukocyte recruitment persisted beyond the very acute phase.

Conclusion: These results demonstrate that the p55-targeting dAb attenuates lung injury and edema formation in models of ARDS induced by acid aspiration, with protection from a single dose lasting up to 24 h. Together with our previous data, the current study lends support toward the clinical targeting of p55 for patients with, or at risk of ARDS.

No MeSH data available.


Respiratory system elastance (A) and resistance (B), and arterial pO2 (C) and pCO2 (D) following acid instillation in animals treated with dummy or p55-targeting dAb. Mechanics data are expressed as % increase following acid. Elastance data (A) were log-transformed to achieve normal distribution, while pO2(C) was normalized by raising to the power of 2. These data are displayed as back-transformed mean with error bars representing 90% confidence intervals. Resistance data and pCO2 were normally distributed and thus displayed as mean ± SD. Repeated measures analysis of variance revealed significant interactions between treatment and time for elastance change (p < 0.01), pO2 (p < 0.05), and pCO2 (p < 0.01). *p < 0.05 between dummy and dAb-treated animals at 180 min after acid. N = 5–6 observations from independent experiments at each time point.
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Figure 2: Respiratory system elastance (A) and resistance (B), and arterial pO2 (C) and pCO2 (D) following acid instillation in animals treated with dummy or p55-targeting dAb. Mechanics data are expressed as % increase following acid. Elastance data (A) were log-transformed to achieve normal distribution, while pO2(C) was normalized by raising to the power of 2. These data are displayed as back-transformed mean with error bars representing 90% confidence intervals. Resistance data and pCO2 were normally distributed and thus displayed as mean ± SD. Repeated measures analysis of variance revealed significant interactions between treatment and time for elastance change (p < 0.01), pO2 (p < 0.05), and pCO2 (p < 0.01). *p < 0.05 between dummy and dAb-treated animals at 180 min after acid. N = 5–6 observations from independent experiments at each time point.

Mentions: The physiological consequences of acid instillation were then compared between animals pretreated with either the dummy non-targeting dAb or the p55-targeting dAb (N = 6 independent experiments/group). The initial mechanics response to acid was similar between the two groups (Figure 2A), consisting of a transient spike in elastance followed by a return toward pre-instillation levels. In the dummy dAb group, elastance then increased from ~100 min until the end, whereas in contrast, the p55-targeting dAb-treated mice showed little increase, resulting in a significantly attenuated elastance change (p value for interaction <0.01, although pairwise analysis did not detect significant differences at individual time points). Respiratory system resistance showed similar patterns in both groups, consisting of a decrease following acid instillation that remained relatively stable thereafter (Figure 2B). There was also a decrease in arterial pO2 and an increase in pCO2 during the final hour of ventilation in dummy-treated animals (Figures 2C,D). These impairments in gas exchange were significantly attenuated by treatment with the p55-targeting dAb (p-value for interaction <0.05, with pairwise analysis showing significant difference at the 180 min time point).


Inhibition of TNF Receptor p55 By a Domain Antibody Attenuates the Initial Phase of Acid-Induced Lung Injury in Mice
Respiratory system elastance (A) and resistance (B), and arterial pO2 (C) and pCO2 (D) following acid instillation in animals treated with dummy or p55-targeting dAb. Mechanics data are expressed as % increase following acid. Elastance data (A) were log-transformed to achieve normal distribution, while pO2(C) was normalized by raising to the power of 2. These data are displayed as back-transformed mean with error bars representing 90% confidence intervals. Resistance data and pCO2 were normally distributed and thus displayed as mean ± SD. Repeated measures analysis of variance revealed significant interactions between treatment and time for elastance change (p < 0.01), pO2 (p < 0.05), and pCO2 (p < 0.01). *p < 0.05 between dummy and dAb-treated animals at 180 min after acid. N = 5–6 observations from independent experiments at each time point.
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Related In: Results  -  Collection

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Show All Figures
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Figure 2: Respiratory system elastance (A) and resistance (B), and arterial pO2 (C) and pCO2 (D) following acid instillation in animals treated with dummy or p55-targeting dAb. Mechanics data are expressed as % increase following acid. Elastance data (A) were log-transformed to achieve normal distribution, while pO2(C) was normalized by raising to the power of 2. These data are displayed as back-transformed mean with error bars representing 90% confidence intervals. Resistance data and pCO2 were normally distributed and thus displayed as mean ± SD. Repeated measures analysis of variance revealed significant interactions between treatment and time for elastance change (p < 0.01), pO2 (p < 0.05), and pCO2 (p < 0.01). *p < 0.05 between dummy and dAb-treated animals at 180 min after acid. N = 5–6 observations from independent experiments at each time point.
Mentions: The physiological consequences of acid instillation were then compared between animals pretreated with either the dummy non-targeting dAb or the p55-targeting dAb (N = 6 independent experiments/group). The initial mechanics response to acid was similar between the two groups (Figure 2A), consisting of a transient spike in elastance followed by a return toward pre-instillation levels. In the dummy dAb group, elastance then increased from ~100 min until the end, whereas in contrast, the p55-targeting dAb-treated mice showed little increase, resulting in a significantly attenuated elastance change (p value for interaction <0.01, although pairwise analysis did not detect significant differences at individual time points). Respiratory system resistance showed similar patterns in both groups, consisting of a decrease following acid instillation that remained relatively stable thereafter (Figure 2B). There was also a decrease in arterial pO2 and an increase in pCO2 during the final hour of ventilation in dummy-treated animals (Figures 2C,D). These impairments in gas exchange were significantly attenuated by treatment with the p55-targeting dAb (p-value for interaction <0.05, with pairwise analysis showing significant difference at the 180 min time point).

View Article: PubMed Central - PubMed

ABSTRACT

Background: Tumor necrosis factor-&alpha; (TNF) is strongly implicated in the development of acute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has been hampered by its complex biology. TNF signals through two receptors, p55 and p75, which play differential roles in pulmonary edema formation during ARDS. We have recently shown that inhibition of p55 by a novel domain antibody (dAb&trade;) attenuated ventilator-induced lung injury. In the current study, we explored the efficacy of this antibody in mouse models of acid-induced lung injury to investigate the longer consequences of treatment.

Methods: We employed two acid-induced injury models, an acute ventilated model and a resolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally or intranasally with p55-targeting dAb or non-targeting &ldquo;dummy&rdquo; dAb, 1 or 4&thinsp;h before acid instillation.

Results: Acid instillation in the dummy dAb group caused hypoxemia, increased respiratory system elastance, pulmonary inflammation, and edema in both the ventilated and resolving models. Pretreatment with p55-targeting dAb significantly attenuated physiological markers of ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in the ventilated model, with signs that altered cytokine production and leukocyte recruitment persisted beyond the very acute phase.

Conclusion: These results demonstrate that the p55-targeting dAb attenuates lung injury and edema formation in models of ARDS induced by acid aspiration, with protection from a single dose lasting up to 24&thinsp;h. Together with our previous data, the current study lends support toward the clinical targeting of p55 for patients with, or at risk of ARDS.

No MeSH data available.