The role of Src & ERK1/2 kinases in inspiratory resistive breathing induced acute lung injury and inflammation

Abstract

BackgroundInspiratory resistive breathing (IRB), a hallmark of obstructive airway diseases, is associated with large negative intrathoracic pressures, due to strenuous contractions of the inspiratory muscles. IRB is shown to induce lung injury in previously healthy animals. Src is a multifunctional kinase that is activated in the lung by mechanical stress. ERK1/2 kinase is a downstream target of Src. We hypothesized that Src is activated in the lung during IRB, mediates ERK1/2 activation and IRB-induced lung injury.MethodsAnaesthetized, tracheostomized adult rats breathed spontaneously through a 2-way non-rebreathing valve. Resistance was added to the inspiratory port to provide a peak tidal inspiratory pressure of 50% of maximum (inspiratory resistive breathing). Activation of Src and ERK1/2 in the lung was estimated during IRB. Following 6 h of IRB, respiratory system mechanics were measured by the forced oscillation technique and bronchoalveolar lavage (BAL) was performed to measure total and differential cell count and total protein levels. IL-1b and MIP-2a protein levels were measured in lung tissue samples. Wet lung weight to total body weight was measured and Evans blue dye extravasation was estimated to measure lung permeability. Lung injury was evaluated by histology. The Src inhibitor, PP-2 or the inhibitor of ERK1/2 activation, PD98059 was administrated 30 min prior to IRB.ResultsSrc kinase was activated 30 min after the initiation of IRB. Src inhibition ameliorated the increase in BAL cellularity after 6 h IRB, but not the increase of IL-1β and MIP-2a in the lung. The increase in BAL total protein and lung injury score were not affected. The increase in tissue elasticity was partly inhibited. Src inhibition blocked ERK1/2 activation at 3 but not at 6 h of IRB. ERK1/2 inhibition ameliorated the increase in BAL cellularity after 6 h of IRB, blocked the increase of IL-1β and returned Evans blue extravasation and wet lung weight to control values. BAL total protein and the increase in elasticity were partially affected. ERK1/2 inhibition did not significantly change total lung injury score compared to 6 h IRB.ConclusionsSrc and ERK1/2 are activated in the lung following IRB and participate in IRB-induced lung injury.

Bioinformatics analysis of the potential biomarkers for acute respiratory distress syndrome

“…Up-regulated genes were mainly involved in regulation of ERK1 and ERK2 cascade, response to interferon-gamma, cell chemotaxis, and migration. This is consistent with earlier studies showing that enhancement of AM immune and inflammatory responses plays a crucial role in ARDS development and progression [12][13][14]. The most significantly enriched of the KEGG pathway up-regulated DEGs were rheumatoid arthritis, cytokine-cytokine receptor interaction, phagosome, and the chemokine signaling pathway.…”

The ERK/CREB pathway is involved in the c-Ski expression induced by low TGF-β1 concentrations during primary fibroblast proliferation

“…Similar to the effects on c-Ski, MEK inhibition did not completely reduce the levels of p-ERK, p-CREB or cell proliferation to that of the control group. This phenomenon may be caused by failure of the MEK inhibitor to completely suppress ERK activity, as found in previous studies [22][23][24]. These data indicate that TGF-β1 is an important factor mediating increases in c-Ski through the ERK/CREB pathway.…”

Ginkgolide C attenuates lipopolysaccharide‑induced acute lung injury by inhibiting inflammation via regulating the CD40/NF‑κB signaling pathway

“…LPS-induced excessive lung inflammation and destruction of the structure and function of alveolar epithelial cells are important pathological processes of ALI, which commonly result in significant morbidity or even death ( 23 ). Augmentation of inflammatory responses in the lung tissue stimulates the production of numerous cytotoxic substances, including various proinflammatory cytokines, ROS and granular enzymes, thereby affecting the development and severity of LPS-induced ALI ( 24 ).…”