High-Density Lipoproteins Potentiate α₁-Antitrypsin Therapy in Elastase-Induced Pulmonary Emphysema

Abstract

Several studies report that high-density lipoproteins (HDLs) can carry α1-antitrypsin (AAT; an elastase inhibitor). We aimed to determine whether injection of exogenous HDL, enriched or not in AAT, may have protective effects against pulmonary emphysema. After tracheal instillation of saline or elastase, mice were randomly treated intravenously with saline, human plasma HDL (75 mg apolipoprotein A1/kg), HDL-AAT (75 mg apolipoprotein A1-3.75 mg AAT/kg), or AAT alone (3.75 mg/kg) at 2, 24, 48, and 72 hours. We have shown that HDL-AAT reached the lung and prevented the development of pulmonary emphysema by 59.3% at 3 weeks (alveoli mean chord length, 22.9 ± 2.8 μm versus 30.7 ± 4.5 μm; P < 0.001), whereas injection of HDL or AAT alone only showed a moderate, nonsignificant protective effect (28.2 ± 4.2 μm versus 30.7 ± 5 μm [P = 0.23] and 27.3 ± 5.66 μm versus 30.71 ± 4.96 μm [P = 0.18], respectively). Indeed, protection by HDL-AAT was significantly higher than that observed with HDL or AAT (P = 0.006 and P = 0.048, respectively). This protective effect was associated (at 6, 24, and 72 h) with: (1) a reduction in neutrophil and macrophage number in the bronchoalveolar lavage fluid; (2) decreased concentrations of IL-6, monocyte chemoattractant protein-1, and TNF-α in both bronchoalveolar lavage fluid and plasma; (3) a reduction in matrix metalloproteinase-2 and matrix metalloproteinase-9 activities; and (4) a reduction in the degradation of fibronectin, a marker of tissue damage. In addition, HDL-AAT reduced acute cigarette smoke-induced inflammatory response. Intravenous HDL-AAT treatment afforded a better protection against elastase-induced pulmonary emphysema than AAT alone, and may represent a significant development for the management of emphysema associated with AAT deficiency.

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

“…In this regard, a recent study has shown that AAT bound to high-density lipoprotein and when administered in a mouse model of pulmonary emphysema afforded greater protection from emphysema than AAT alone (82). The advantages included a reduction in airway neutrophil and macrophage counts, decreased IL-6, MCP-1, and TNF-a levels, as well as a reduction in MMP activity and degradation of fibronectin (82). AAT can also interact with the iron atom in heme (83) and CD16b on membrane lipid rafts of circulating neutrophils (29).…”

Urine Specific Proteins and Alpha-1 Antitrypsin Concentrations to Assess the Severity of Lupus Nephritis

“…The AAT concentrations in serum may vary depending on the condition of an individual, with normal values ranging from 1.5 to 3.5 g/L (or from 20 to 48 μM). The amount of research on AAT-associated renal diseases is still very small (Moreno et al, 2014;Ortiz et al, 2014;Zager et al, 2014).…”

α-Linoleic Acid Enhances the Capacity of α1-Antitrypsin to Inhibit Lipopolysaccharide-Induced IL-1β in Human Blood Neutrophils

“…For example, biological activities of A1AT can be modified due to interactions with lipid moieties, in which A1AT was found in association with cell membrane lipid rafts (19,20) and was detected in complexes with low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs). (21,22) The binding of A1AT to HDL augments its protective effect in a mouse model of elastase-induced pulmonary emphysema. (22) We recently reported that A1AT purified from human plasma binds polyunsaturated fatty acids (FAs) like α-linoleic and oleic acid, and that only FA-bound forms of A1AT increase the expression and release of ANGPTL4 in human bloodadherent monocytic cells and in primary human lung microvascular endothelial cells.…”

“…(21,22) The binding of A1AT to HDL augments its protective effect in a mouse model of elastase-induced pulmonary emphysema. (22) We recently reported that A1AT purified from human plasma binds polyunsaturated fatty acids (FAs) like α-linoleic and oleic acid, and that only FA-bound forms of A1AT increase the expression and release of ANGPTL4 in human bloodadherent monocytic cells and in primary human lung microvascular endothelial cells. (23,24) The above functional differences between FA-free and FA-bound forms of A1AT led us to hypothesize that these 2 forms may express distinct immunomodulatory activities during neutrophil activation.…”