Primary lung graft dysfunction could significantly attribute to ischemia-reperfusion lung injury (IRLI) during transplantation surgery. β2-adrenergic agonists were one of the bronchodilators that had been well-established in the management of asthma and chronic obstructive pulmonary disease (COPD) with anti-inflammatory potency. By applying the model of isolated rat lung, we evaluated the efficacy of short-acting β2-agonist inhalation to ameliorate ischemia-reperfusion damage. The experiment protocol was 180 min of global ischemia and then reperfusion for 60 min. In the β2-agonist inhalation group, aerosolized albuterol was administrated prior ischemia procedure.Increased weight ratios of wet to dry lung and microvascular permeability were characterized in the IRLI group. In contrast, pre-inhaled β2-agonist significantly mitigated the severity of pulmonary edema. Bronchoalveolar lavage from the β2-agonist group presented decreased leukocyte counts and cytokines production, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein 2 (MIP-2). Devastating oxidative stress was widely recognized during the ischemia-reperfusion process, while β2-agonist pretreatment revealed subsided H 2 O 2 , myeloperoxidase (MPO), and the cleavage of caspase-3. Western blotting from lung homogenates identified the blockade of NF-κB and MAPK activation in the β2-agonist inhalation group. Currently, there was no specific pharmacotherapy in IRLI management. Our results elucidated the protective effect of β2-agonist bronchodilator against ischemia-reperfusion induced oxidative stress, inflammation reaction, and pulmonary edema.
Malignant-associated pleural fluid (MAPF) represented an unsolved problem in advanced lung cancer. Our previous work characterized increased pleural angiogenesis in lung adenocarcinoma and the propensity of MAPF on endothelial angiogenesis. This study investigated the combined efficacy of the tyrosine kinase inhibitor (gefitinib) and bevacizumab in opposing MAPF-induced angiogenesis. In lung adenocarcinoma patients with malignant pleural effusion (MPE), Kaplan–Meier analysis revealed the benefit of cotreatment with target therapy and bevacizumab. Increased EGFR expression was observed in the pleural microvessels of patients with lung adenocarcinoma both with and without mutations in EGFR. MAPF was obtained from lung adenocarcinoma patients both wild-type and mutant EGFRs. Total and phosphorylated EGFR were upregulated in HUVEC cultured with MAPF. Treatment with gefitinib as an EGFR inhibitor suppressed MAPF-induced endothelial migration and partially attenuated endothelial proliferation in both wild-type and mutant EGFR lung adenocarcinoma. Cotreatment with gefitinib and bevacizumab produced better inhibition of MAPF-induced endothelial angiogenesis than gefitinib alone in the mutant EGFR subgroup. Protein analysis of MAPF-derived exosomes revealed abundant EGFR and p-EGFR components that implied possible transfer to endothelial cells. Concluding Kaplan–Meier analysis and in vitro studies, the results indicated that the addition of bevacizumab on gefitinib treatment could suppress MAPF-induced angiogenesis in lung adenocarcinoma patients.
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