Cigarette smoke-induced lung endothelial apoptosis and emphysema are associated with impairment of FAK and eIF2α.
Lung endothelial cell (EC) apoptosis has been implicated in the pathogenesis of emphysema. However, the mechanism underlying cigarette smoke (CS)-induced lung EC apoptosis and emphysema is not well defined. We have previously shown that cigarette smoke extract (CSE) decreased focal adhesion kinase (FAK) activity via oxidative stress in cultured lung EC. In this study, we compared FAK activation in the lungs of highly susceptible AKR mice and mildly susceptible C57BL/6 mice after exposure to CS for three weeks. We found that three weeks of CS exposure caused mild emphysema and increased lung EC apoptosis in AKR mice (room air: 12.8±5.6%; CS: 30.7±3.7%), but not in C57BL/6 mice (room air: 0±0%; CS: 3.5±1.7%). Correlated with increased lung EC apoptosis and early onset of emphysema, FAK activity was reduced in the lungs of AKR mice, but not of C57BL/6 mice. Additionally, inhibition of FAK caused lung EC apoptosis, whereas over-expression of FAK prevented CSE-induced lung EC apoptosis. These results suggest that FAK inhibition may contribute to CS-induced lung EC apoptosis and emphysema. Unfolded protein response (UPR) and autophagy have been shown to be activated by CS exposure in lung epithelial cells. In this study, we noted that CSE activated UPR and autophagy in cultured lung EC, as indicated by enhanced eIF2α phosphorylation and elevated levels of GRP78 and LC3B-II. However, eIF2α phosphorylation was significantly reduced by three-weeks of CS exposure in the lungs of AKR mice, but not of C57BL/6 mice. Markers for autophagy activation were not significantly altered in the lungs of either AKR or C57BL/6 mice. These results suggest that CS-induced impairment of eIF2α signaling may increase the susceptibility to lung EC apoptosis and emphysema. Taken together, our data suggest that inhibition of eIF2α and FAK signaling may play an important role in CS-induced lung EC apoptosis and emphysema.
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, RI 02908, USA.
Pavlo
P
Sakhatskyy
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, RI 02908, USA.
Gustavo Andres
GA
Gabino Miranda
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, RI 02908, USA.
Julie
J
Newton
Pulmonary, Critical Care and Sleep Medicine, School of Medicine, Yale University, New Haven, CT 06520, USA.
Chun Geun
CG
Lee
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, RI 02908, USA.
Gaurav
G
Choudhary
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, RI 02908, USA.
Alexander
A
Vang
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, RI 02908, USA.
Sharon
S
Rounds
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School of Brown University, Providence, RI 02908, USA. Electronic address: Qing_Lu@brown.edu.
Qing
Q
Lu
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002417:Cattle; D002478:Cells, Cultured; D004646:Emphysema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D018384:Oxidative Stress; D010766:Phosphorylation; D051381:Rats; D012906:Smoke / Q000009:adverse effects*; D013997:Time Factors; D056811:Unfolded Protein Response
D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D012906:Smoke; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse
AKR mice; Apoptosis; Autophagy; Cigarette smoke; Emphysema; Endothelial cell; Focal adhesion kinase; Lung; Unfolded protein response; eIF2alpha