Intranasal Application of Budesonide Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Suppressing Nucleotide-Binding Oligomerization Domain-Like Receptor Family, Pyrin Domain-Containing 3 Inflammasome Activation in Mice

Abstract

Aim. To investigate the protective effects of budesonide against lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in a murine model and its underlying mechanism. Methods. Adult male C57BL/6 mice were divided into three groups: control, ALI, and ALI + budesonide groups. LPS (5 mg/kg) was intratracheally injected to induce ALI in mice. Budesonide (0.5 mg/kg) was intranasally given 1 h before LPS administration in the ALI + budesonide group. Twelve hours after LPS administration, all mice were sacrificed. Hematoxylin-eosin staining and pathological scores were used to evaluate pathological injury. Bronchoalveolar lavage was performed. The numbers of total cells, neutrophils, and macrophages in the bronchoalveolar lavage fluid (BALF) were counted. Enzyme-linked immunosorbent assay was employed to detect the proinflammatory cytokines in BALF and serum, including tumor necrosis factor- (TNF-) α, monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 1β. The expression of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome was detected by western blotting. A lethal dose of LPS (40 mg/kg, intraperitoneally) was injected to evaluate the effects of budesonide on survival rates. Results. Budesonide pretreatment dramatically attenuated pathological injury and reduced pathological scores in mice with ALI. Budesonide pretreatment obviously reduced the numbers of total cells, neutrophils, and macrophages in the BALF of mice with ALI. Additionally, budesonide dramatically reduced TNF-α and MCP-1 expression in the BALF and serum of mice with ALI. Budesonide significantly suppressed NLRP3 and pro-caspase-1 expression in the lung and reduced IL-1β content in the BALF, indicating that budesonide inhibited the activation of the NLRP3 inflammasome. Furthermore, we found that budesonide improved the survival rates of mice with ALI receiving a lethal dose of LPS. Conclusion. Suppression of NLRP3 inflammasome activation in mice via budesonide attenuated lung injury induced by LPS in mice with ALI.

Anti-Inflammatory Effects of the Iron Chelator, DIBI, in Experimental Acute Lung Injury

“…The degree of inflammation was then assessed and scored based on the presence of edema, hemorrhage, immune cells infiltration, cell wall thickening and the presence of aggregates. Scoring scale: 0, minimum damage; 1, mild damage; 2, moderate damage; 3, severe damage; and 4, intense damage [3].…”

“…Lung injury can be induced directly (locally), as in pneumonia, smoke inhalation, and aspiration, with mainly epithelial injury, or indirectly (systemically), induced by blood-borne insults like sepsis and pancreatitis with mainly endothelial injury [2]. ARDS results in disruption of the lung endothelial and epithelial barriers inducing increased pulmonary permeability, and impairment of pulmonary gas exchange [3]. Importantly, ARDS represents a complication of pneumonia caused by the virus SARS-CoV-2, and a significant number of patients with severe COVID-19 suffer from its consequences [4,5].…”

Early local neutralization of CC16 in sepsis‑induced ALI following blunt chest trauma leads to delayed mortality without benefitting overall survival

“…With regard to the two-hit hypothesis, the inflammatory response following trauma is essential for host defense; however, it can cause further tissue damage if triggered by a secondary stimulus ( 22 , 23 ). Since reducing inflammation attenuates pathological injury and the survival of mice with ALI ( 24 ), as a pulmonary anti-inflammatory protein, CC16 may play an important regulatory role during the development ALI following trauma. However, CC16 may also play a pathological role in immunoparalysis with concomitant post-traumatic infectious complications ( 25 ).…”

Early Local Inhibition of Club Cell Protein 16 Following Chest Trauma Reduces Late Sepsis-Induced Acute Lung Injury

“…It is well-established that an inflammatory response after trauma is essential for host defense, but that it can cause further tissue damage if triggered by a secondary stimulus [21,22]. Reducing the inflammation attenuated the pathological injury and survival upon ALI, in mice [23]. On the other hand, immunoparalysis, which has been closely associated with posttraumatic infectious complications, is caused by an anti-inflammatory status of the organism, and CC16 as a strong local anti-inflammatory factor might play a pathological role here [24,25,26].…”