Obesity is a worldwide epidemic problem and correlates to varieties of acute or chronic lung diseases such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, and pulmonary fibrosis. An increase of leptin, a kind of adipokine, in lean mice plasma has been found to impair immune responses and facilitate the infection of Klebsiella pneumoniae, resulting in increased pneumonia severity. Also, a higher leptin level is found in exhaled breath condensates of obese or asthmatic subjects, compared to healthy ones, suggesting that leptin is involved in the occurrence or exacerbation of lung injury. In previous studies, we showed that leptin stimulated cytosolic phospholipase A2-α (cPLA2α) gene expression in lung alveolar type II cells via mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB)-activated coactivator p300. Herein, we show that the in vivo application of leptin in the respiratory system upregulated the expression of inflammatory proteins cPLA2α and cyclooxygenase-2 (COX-2) together with leukocyte infiltration. Treatment with an ROS scavenger (N-acetylcysteine, NAC), an NADPH oxidase inhibitor (apocynin), or an activating protein (AP)-1 inhibitor (tanshinone IIA) attenuated leptin-mediated cPLA2α/COX-2 expression and leukocyte recruitment in the lung. Leptin increased intracellular oxidative stress in a leptin receptor (OB-R) and NADPH oxidase-dependent manner, leading to the phosphorylation of the AP-1 subunit c-Jun. In summation, leptin increased lung cPLA2α/COX-2 expression and leukocyte recruitment via the NADPH oxidase/ROS/AP-1 pathway. Understanding the inflammatory effects of leptin on the pulmonary system provides opportunities to develop strategies against lung injury related to metabolic syndrome or obesity.

Hyperplasia or hypertrophy of adipose tissues plays a crucial role in obesity, which is accompanied by the release of leptin. Recently, obesity was determined to be associated with various pulmonary diseases including asthma, acute lung injury, and chronic obstructive pulmonary disease. However, how obesity contributes to pulmonary diseases and whether leptin directly regulates lung inflammation remains unclear. We used cell and animal models to study the mechanisms of leptin mediation of pulmonary inflammation. We found that leptin activated de novo synthesis of cytosolic phospholipase A₂-α (cPLA₂-α) in vitro in the lung alveolar type II cells, A549, and in vivo in ICR mice. Upregulated cPLA₂-α protein was attenuated by pretreatment with an OB-R blocking antibody, U0126, SB202190, SP600125, Bay11-7086, garcinol, and p300 siRNA, suggesting roles of p42/p44 MAPK, p38 MAPK, JNK1/2, NF-κB, and p300 in leptin effects. Leptin enhanced the activities of p42/p44 MAPK, p38 MAPK, JNK1/2, and p65 NF-κB in a time-dependent manner. Additional studies have suggested the participation of OB-R, p42/p44 MAPK, and JNK1/2 in leptin-increased p65 phosphorylation. Furthermore, p300 phosphorylation and histone H4 acetylation were reduced by blockage of OB-R, p42/p44 MAPK, p38 MAPK, JNK1/2, and NF-κB in leptin-stimulated cells. Similarly, blockage of the MAPKs/NF-κB/p300 cascade significantly inhibited leptin-mediated cPLA₂-α mRNA expression. Our data as a whole showed that leptin contributed to lung cPLA₂-α expression through OB-R-dependent activation of the MAPKs/NF-κB/p300 cascade.

Background/Objectives: Albumin supplementation is widely used for hypoalbuminemia treatment in patients with critical illness, especially those with cirrhosis. However, studies have demonstrated that routine albumin administration is not always advantageous. We examined how albumin supplementation affects survival outcomes in patients with sepsis with hypoalbuminemia. Methods: This study was conducted by researchers in Taiwan using data from the TriNetX research platform, covering the period from 1 April 2014 to 30 April 2024. This platform aggregates real-world data from healthcare organizations worldwide. From this dataset, 1,147,433 patients who developed sepsis and hypoalbuminemia with albumin levels <3.5 g/dL were identified. The study population was stratified into two groups on the basis of whether they received albumin infusion or not. To compare outcomes, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated between propensity-score-matched patients who did and did not receive albumin supplementation. Subgroup analysis by albumin levels was conducted. Results: Albumin infusion was linked to increased risks of 30-day mortality (HR [95% CI] = 1.800 [1.774–1.827], p < 0.05), shock (HR [95% CI] = 1.436 [1.409–1.465], p < 0.05), septic shock (HR [95% CI] = 1.384 [1.355–1.415], p < 0.05), hypovolemic shock (HR [95% CI] = 1.496 [1.391–1.608], p < 0.05), cardiogenic shock (HR [95% CI] = 1.553 [1.473–1.637], p < 0.05), heart failure (HR [95% CI] = 1.098 [1.080–1.116], p < 0.05), and pulmonary edema (HR [95% CI] = 1.479 [1.438–1.520], p < 0.05). The subgroup analysis by albumin levels revealed a trend of increased mortality risk with albumin supplementation in patients with high baseline albumin levels. Conclusions: Patients with sepsis with hypoalbuminemia who received albumin supplementation exhibited high 30-day mortality rates and increased risks of shock, heart failure, and pulmonary edema compared with those who did not. These findings indicate that routine albumin administration may be linked with unfavorable outcomes in these patients.