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. 2020 Mar;32(1):58-65.
doi: 10.5935/0103-507x.20200010. Epub 2020 May 8.

Pretreatment with adalimumab reduces ventilator-induced lung injury in an experimental model

[Article in English, Portuguese]
Enrique Correger  1 , Josefina Marcos  1 , Graciela Laguens  2 , Pablo Stringa  1 , Pablo Cardinal-Fernández  3 , Lluis Blanch  4
Affiliations

Pretreatment with adalimumab reduces ventilator-induced lung injury in an experimental model

[Article in English, Portuguese]
Enrique Correger et al. Rev Bras Ter Intensiva. 2020 Mar.

Abstract
in English, Portuguese

Objective: To determine whether adalimumab administration before mechanical ventilation reduces ventilator-induced lung injury (VILI).

Methods: Eighteen rats randomized into 3 groups underwent mechanical ventilation for 3 hours with a fraction of inspired oxygen = 0.40% including a low tidal volume group (n = 6), where tidal volume = 8mL/kg and positive end-expiratory pressure = 5cmH2O; a high tidal volume group (n = 6), where tidal volume = 35mL/kg and positive end-expiratory pressure = 0; and a pretreated + high tidal volume group (n = 6) where adalimumab (100ug/kg) was administered intraperitoneally 24 hours before mechanical ventilation + tidal volume = 35mL/kg and positive end-expiratory pressure = 0. ANOVA was used to compare histological damage (ATS 2010 Lung Injury Scoring System), pulmonary edema, lung compliance, arterial partial pressure of oxygen, and mean arterial pressure among the groups.

Results: After 3 hours of ventilation, the mean histological lung injury score was higher in the high tidal volume group than in the low tidal volume group (0.030 versus 0.0051, respectively, p = 0.003). The high tidal volume group showed diminished lung compliance at 3 hours (p = 0.04) and hypoxemia (p = 0,018 versus control). Pretreated HVt group had an improved histological score, mainly due to a significant reduction in leukocyte infiltration (p = 0.003).

Conclusion: Histological examination after 3 hours of injurious ventilation revealed ventilator-induced lung injury in the absence of measurable changes in lung mechanics or oxygenation; administering adalimumab before mechanical ventilation reduced lung edema and histological damage.

Objetivo: Determinar se a administração de adalimumabe previamente à ventilação mecânica reduz a lesão pulmonar induzida por ventilação mecânica.

Métodos: Randomizaram-se 18 ratos em três grupos submetidos à ventilação mecânica por 3 horas com uma fração inspirada de oxigênio de 0,40%. Os três grupos foram assim caracterizados: um grupo com baixo volume corrente (n = 6), no qual se utilizaram volume corrente de 8mL/kg e pressão expiratória final positiva de 5cmH2O; um grupo com alto volume corrente (n = 6), no qual se utilizaram volume corrente de 35mL/kg e pressão expiratória final positiva de zero; e um grupo pré-tratado com alto volume corrente (n = 6), no qual se administraram adalimumabe (100µg/kg) por via intraperitoneal 24 horas antes do início da ventilação mecânica, volume corrente de 35mL/kg e pressão expiratória final positiva de zero. Realizou-se ANOVA para comparação de dano histológico (com utilização de escores segundo o ATS 2010 Lung Injury Scoring System), edema pulmonar, complacência pulmonar, pressão parcial de oxigênio arterial e pressão arterial média entre os grupos.

Resultados: Após 3 horas de ventilação, o escore médio de lesão histológica pulmonar foi mais elevado no grupo com alto volume corrente do que no grupo com baixo volume corrente (0,030 versus 0,0051; p = 0,003). O grupo com alto volume corrente demonstrou complacência pulmonar diminuída após 3 horas (p = 0,04) e hipoxemia (p = 0,018 versus controle). O grupo alto volume corrente tratado previamente teve melhora do escore histológico, principalmente devido à redução significante da infiltração leucocitária (p = 0,003).

Conclusão: O exame histológico após 3 horas de ventilação lesiva revelou lesão pulmonar induzida por ventilação mecânica na ausência de modificações mensuráveis na mecânica pulmonar e na oxigenação; a administração de adalimumabe antes da ventilação mecânica diminuiu o edema pulmonar e o dano histológico.

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Conflict of interest statement

Conflicts of interest: None.

Figures

Figure 1
Figure 1
Macro and microscopic evaluation of lungs. (A) Histological scores of the three groups: low tidal volume, high tidal volume, and adalimumab + high tidal volume. (B) Discrimination of the American Thoracic Society Lung Injury Scoring System variables. (C) Top images: light microscopy, hematoxylin and eosin, original magnification: 40x. Left (low tidal volume group): normal lung architecture tissue. Middle (high tidal volume group): lungs with intraalveolar and interstitial leukocyte infiltration, hyaline membrane formation and septal thickening. Right (adalimumab + high tidal volume group): septal thickening with reduced leukocyte infiltration. Bottom pictures: Gross examination. Left (low tidal volume): normal lungs. Middle (high tidal volume): edema and hemorrhage. Right (adalimumab + high tidal volume): minimal congested areas. Vt - tidal volume; ADA - adalimumab; AST - alveolar septal tickening
Figure 2
Figure 2
Microscopic lung images (A) Detached alveolar coat cell (arrow) and fibrous intraalveolar walls in the process of repair (circle). Microscopic images from the adalimumab + high tidal volume group. (B) Apoptotic bodies recognized and digested by alveolar macrophages. This phenomenon is triggered by specific cell membrane receptors. Microscopic images from the adalimumab + high tidal volume group.
Figure 3
Figure 3
Monitoring during the experimental procedure. Changes in thoracic system compliance, mean arterial pressure and the partial pressure of arterial oxygen: ventilation with a high tidal volume was associated with decreased thoracic system compliance at 3 hours (p = 0.04), and comparison of the high tidal volume group versus the adalimumab + high tidal volume group showed no differences regarding lung compliance (p = 0,26). All groups presented a mean arterial pressure drop over the 3 hours of the study with no significant differences. Ventilation with a high tidal volume was associated with hypoxemia compared with ventilation with a low tidal volume (p = 0.018), while the adalimumab-treated group showed no statistically significant differences at 3 hours compared with the high tidal volume group (p = 0.42). MAP - mean arterial pressure; PaO2 - partial pressure of arterial oxygen; Vt - tidal volume; TNF-α - tumor necrosis factor alpha.
See this image and copyright information in PMC

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