Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a pulmonary disease with high mortality associated with inflammation. During the development of ALI/ARDS, macrophages usually polarize toward M1 pro-inflammatory macrophages, promoting the inflammatory response in ALI/ARDS and aggravating lung tissue damage. Natural compounds with anti-inflammatory activity have achieved excellent results in the treatment of ALI/ARDS through different regulatory modes, including macrophage polarization. Of note, flavonoid, brevilin A, and tetrahydropalmatine play an important role in the treatment of ALI/ARDS by modulating the phenotypic polarization of macrophages and their pro-inflammatory cytokine expression in innate immune cells of the lung. Flavonoids are a kind of naturally occurring polyphenol compound, which has antioxidant and anti-inflammatory activities. Studies have found that some flavonoids can alleviate ALI/ARDS through inhibiting the expression of inflammatory cytokines in macrophages. Among them, 5-methoxyflavone, acacetin, grape seed proanthocyanidins, and luteolin can also regulate macrophage polarization. Therefore, the in-depth exploration of the regulatory mechanism of macrophages can lay the foundation for the application of flavonoids in alleviating inflammation-related lung injury. This review focuses on the macrophage polarization effects of different natural compounds and their potential anti-inflammatory mechanisms in the treatment of ALI/ARDS.

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), remain critical clinical challenges characterized by acute diffuse lung inflammation, alveolar-capillary barrier disruption, and refractory pulmonary edema, leading to high morbidity and mortality. The alveolar epithelium, a key structural and functional unit of the lung, plays a pivotal role in maintaining alveolar fluid homeostasis, which depends on coordinated transcellular ion transport and paracellular barrier integrity mediated primarily by the epithelial sodium channel (ENaC) and tight junction proteins. As a central regulator of alveolar fluid clearance, ENaC mediates sodium ion reabsorption across the alveolar epithelium, whereas tight junction proteins, including zonula occludens-1, occludin, and claudins, restrict paracellular leakage and maintain epithelial barrier integrity. In the pathological setting of ALI/ARDS, both ENaC and tight junction proteins undergo significant dysregulation, with reduced ENaC function leading to impaired alveolar fluid clearance and exacerbated edema, while alterations in the expression, distribution, and function of tight junction proteins further compromise barrier integrity. Despite their individual roles being increasingly recognized, the complex interplay between ENaC and tight junctions in the alveolar fluid homeostasis of ALI/ARDS, as well as the underlying regulatory mechanisms, remain incompletely understood. This review therefore focuses on the mechanistic and functional crosstalk between ENaC and tight junction proteins, integrating their coordinated roles in alveolar fluid transport, barrier dysfunction, and pulmonary edema, and discussing potential therapeutic strategies with this coupled regulatory system in ALI/ARDS.