Inhibition of BTK protects lungs from trauma-hemorrhagic shock-induced injury in rats

Abstract

The present study aimed to investigate the role of Bruton's tyrosine kinase (BTK) in the pathogenesis of lung injury induced by trauma-hemorrhagic shock (THS), and to examine the pulmonary protective effects of BTK inhibition. Male Sprague-Dawley rats were divided into four groups (n=12/group): i) A Sham group, which received surgery without induced trauma; ii) a THS-induced injury group; iii) a THS-induced injury group that also received treatment with the BTK inhibitor LFM-A13 prior to trauma induction; and iv) a Sham group that was pretreated with LFM-A13 prior to surgery but did not receive induced trauma. The expression of phosphorylated-BTK protein in the lungs was measured by immunohistochemistry and western blot analysis. The bronchoalveolar lavage fluid (BALF) protein concentration, total leukocyte and eosinophil numbers, and the expression levels of peripheral blood proinflammatory factors were measured. Morphological alterations in the lungs were detected by hematoxylin and eosin staining. Pulmonary nitric oxide (NO) concentration and inducible NO synthase (iNOS) expression were also assessed. Activities of the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways were determined by western blotting or electrophoretic mobility shift assay. BTK was notably activated in lungs of THS rats. BALF protein concentration, total leukocytes and eosinophils, peripheral blood expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and monocyte chemotactic protein 1 were significantly upregulated after THS induction, and each exhibited decreased expression upon LFM-A13 treatment. THS-induced interstitial hyperplasia, edema and neutrophilic infiltration in lungs were improved by the inhibition of BTK. In addition, THS-induced NO release, iNOS overexpression, and NF-κB and MAPK signaling were suppressed by BTK inhibition. Results from the present study demonstrate that BTK may serve a pivotal role in the pathogenesis of THS-related lung injury, and the inhibition of BTK may significantly alleviate THS-induced lung damage. These results provide a potential therapeutic application for the treatment of THS-induced lung injury.

Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses in the lung during murine pneumococcal pneumonia

“…The results of the present study are in line with previously published work showing that inhibition of Btk protected against acute lung injury evoked by polymicrobial sepsis (Zhou et al, 2014), the combination of lipopolysaccharide and immune complexes (Krupa et al, 2014) or the combination of trauma and hemorrhagic shock (Liu et al, 2017). Recently, it was described that intranasal administration of ibrutinib ameliorated survival and decreased lung pathology, PMN influx, neutrophil extracellular trap formation, plasma leakage and cytokine production after influenza infection (Florence et al, 2018).…”

Anti-inflammatory effect of tranexamic acid against trauma-hemorrhagic shock-induced acute lung injury in rats

“…Multiple pathways are involved in the inflammatory response, such as mitogen-activated protein kinase (MAPK) [ 17 ], phosphoinositide 3-kinase (PI3K) [ 12 ], Akt [ 29 ], and mammalian target of rapamycin (mTOR) [ 9 ]. Moreover, several previous studies have demonstrated that aberrant activation of pro-inflammatory toll-like receptor-4 (TLR4) [ 26 ], high-mobility group box 1 (HMGB1) [ 16 ], and NF-kB [ 21 ] pathways is linked to T/HS-associated ALI. NF-κB is a family that contains five members: NF-κB1 (p105/p50), NF-κB2 (p100/p52), RelA (p65), RelB, and c-Rel.…”

Relevance of the Bruton Tyrosine Kinase as a Target for COVID-19 Therapy

“…The overexpression of phosphorylated BTK in the lungs is associated with lung injury, and the induction of an acute respiratory distress syndrome has been reported (75)(76)(77). Accordingly, BTK has been proposed to be involved in sepsis-induced acute lung injury (75).…”

“…The latest experimental evidence also shows that BTK is involved in traumahemorrhagic shock-induced lung injury in rats, and blocking BTK activity with the LFM-A13 inhibitor protects lungs from this injury (77). In addition, at least one study has shown that BTK overexpression in lung is associated with collagen deposition around airways and total basal membrane thickness, suggesting a role for BTK in reducing airway stiffness and increased airway resistance (44).…”