Abstract
BackgroundPulmonary inflammation and endothelial barrier permeability increase in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) induced by pro-inflammatory cytokines and matrix metalloproteinases (MMPs). However, the relationship between pro-inflammatory cytokines and MMPs in ALI/ARDS remains poorly understood.MethodsA lipopolysaccharide (LPS)-induced ALI rat model was established through intratracheal instillation. The wet/dry ratios of lung tissues were measured, and bronchoalveolar lavage fluid (BALF) was collected to test protein concentrations, total cell/macrophage numbers, and pro-inflammatory cytokine levels. LPS-treated alveolar macrophages were utilized in in vitro experiments. The expression and secretion of MMPs were respectively detected using quantitative PCR, Western blotting and ELISA assays.ResultsThe levels of IL-33 and MMP2/9 in BALF increased in all the ALI rats with severe lung injury. LPS-induced IL-33 autocrine upregulated the expression of MMP2 and MMP9 through activating STAT3. Neutralizing IL-33 in culture medium with specific antibodies suppressed the expression and secretion of MMP2 and MMP9 in LPS-treated alveolar macrophages. Consistently, eliminating IL-33 decreased the levels of MMP2 and MMP9 in BALF and alleviated lung injury in ALI rats.ConclusionThe IL-33/STAT3/MMP2/9 regulatory pathway is activated in alveolar macrophages during acute lung injury, which may exacerbate the pulmonary inflammation.
Highlights
Pulmonary inflammation and endothelial barrier permeability increase in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) induced by pro-inflammatory cytokines and matrix metalloproteinases (MMPs)
We purified the alveolar macrophages (AMs) with positive F4/80 staining from bronchoalveolar lavage fluid (BALF)
LPS induced secretion of IL-33, TNF-α, MMP2, MMP9, and TIMP1 in Alveolar macrophages (AMs) cell line NR8383 Considering the critical role of AMs in regulating pro-inflammatory events during ALI, we examined the effect of LPS on the secretion of IL-33, TNF-α, MMP2, and MMP9 in the AM cell line NR8383
Summary
Pulmonary inflammation and endothelial barrier permeability increase in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) induced by pro-inflammatory cytokines and matrix metalloproteinases (MMPs). Disruption of the alveolar–capillary unit, breakdown of the barrier, and gas exchange are clinical manifestations of ALI/ARDS [3]. New therapies, such as extracorporeal membrane oxygenation and lung protective ventilation strategy, have been applied, the. Pro-inflammatory immune cells and the cytokines released by them can increase the permeability of the alveolar–capillary barrier, leading to pulmonary dysfunction [5]. The plasma level of IL-33 was found to be higher in ALI patients than in the healthy [9]. This evidence suggests a potential association between IL-33 and ALI
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