Leptin as regulator of pulmonary immune responses: involvement in respiratory diseases

Leptin is an adipocyte-derived hormone, recognized as a critical mediator of the balance between food intake and energy expenditure by signalling through its functional receptor (Ob-Rb) in the hypothalamus. Structurally, leptin belongs to the long-chain helical cytokine family, and is now known to have pleiotropic functions in both innate and adaptive immunity. The presence of the functional leptin receptor in the lung together with evidence of increased airspace leptin levels arising during pulmonary inflammation, suggests an important role for leptin in lung development, respiratory immune responses and eventually pathogenesis of inflammatory respiratory diseases. The purpose of this article is to review our current understanding of leptin and its functional role on the different resident cell types of the lung in health as well as in the context of three major respiratory conditions being chronic obstructive pulmonary disease (COPD), asthma, and pneumonia

AIBP augments cholesterol efflux from alveolar macrophages to surfactant and reduces acute lung inflammation

Acute respiratory distress syndrome (ARDS) is characterized by an excessive pulmonary inflammatory response. Removal of excess cholesterol from the plasma membrane of inflammatory cells helps reduce their activation. The secreted apolipoprotein A-I binding protein (AIBP) has been shown to augment cholesterol efflux from endothelial cells to the plasma lipoprotein HDL. Here, we find that AIBP was expressed in inflammatory cells in the human lung and was secreted into the bronchoalveolar space in mice subjected to inhalation of LPS. AIBP bound surfactant protein B and increased cholesterol efflux from alveolar macrophages to calfactant, a therapeutic surfactant formulation. In vitro, AIBP in the presence of surfactant reduced LPS-induced p65, ERK1/2 and p38 phosphorylation, and IL-6 secretion by alveolar macrophages. In vivo, inhalation of AIBP significantly reduced LPS-induced airspace neutrophilia, alveolar capillary leak, and secretion of IL-6. These results suggest that, similar to HDL in plasma, surfactant serves as a cholesterol acceptor in the lung. Furthermore, lung injury increases pulmonary AIBP expression, which likely serves to promote cholesterol efflux to surfactant and reduce inflammation

Hyperleptinemia is associated with impaired pulmonary host defense

We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this effect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia