High-density lipoproteins potentiate α1-antitrypsin therapy in elastase-induced pulmonary emphysema.
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.
1 Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)1148, DHU FIRE (Département Hospitalo-Universitaire Fibrosis, Inflammation, REmodeling in cardiovascular, respiratory and renal diseases), Paris, France.
Juan-Antonio
JA
Moreno
Almudena
A
Ortega-Gomez
Alfonso
A
Rubio-Navarro
Liliane
L
Louedec
Benoit
B
Ho-Tin-Noé
Giuseppina
G
Caligiuri
Antonino
A
Nicoletti
Angelique
A
Levoye
Laurent
L
Plantier
Olivier
O
Meilhac
D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007275:Injections, Intravenous; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010196:Pancreatic Elastase; D011014:Pneumonia / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage / Q000494:pharmacology*
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D005353:Fibronectins; D018836:Inflammation Mediators; D008075:Lipoproteins, HDL; D012906:Smoke; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
elastase; emphysema; high-density lipoprotein; α1-antitrypsin