TY - JOUR
T1 - Sepsis induces extensive autophagic vacuolization in hepatocytes
T2 - A clinical and laboratory-based study
AU - Watanabe, Eizo
AU - Muenzer, Jared T.
AU - Hawkins, William G.
AU - Davis, Christopher G.
AU - Dixon, David J.
AU - McDunn, Jonathan E.
AU - Brackett, Daniel J.
AU - Lerner, Megan R.
AU - Swanson, Paul E.
AU - Hotchkiss, Richard S.
N1 - Funding Information:
This work was supported by National Institutes of Health grants GM055194, GM044118, K08 GM084143, and the Alan A and Edith L Wolff Foundation.
PY - 2009/5
Y1 - 2009/5
N2 - Autophagy is the regulated process cells use to recycle nonessential, redundant, or inefficient components and is an adaptive response during times of stress. In addition to its function in enabling the cell to gain vital nutrients in times of stress, autophagy can also be involved in elimination of intracellular microorganisms, tumor suppression, and antigen presentation. Because of difficulty in diagnosing autophagy, few clinical studies have been performed. This study examined whether autophagy occurs in hepatocytes during sepsis. Electron microscopy (EM) was performed on liver samples obtained from both an observational clinical cohort of six septic patients and four control patients as well as liver specimens from mice with surgical sepsis (by cecal ligation and puncture) or sham operation. EM demonstrated increased autophagic vacuoles in septic vs nonseptic patients. Randomly selected fields (3000μm2) from control and septic patients contained 1.2±1.5 vs 5.3±3.3 (mean±s.d.) complex lysosomal autophagolysosomal structures per image respectively (P0.001). In rare instances, hepatocytes with autophagic vacuoles appeared to be unequivocally committed to death. Membrane alterations (membrane vacuoles, invagination into adjacent organelles, and myelin figure-like changes) occur in a subpopulation of mitochondria in sepsis, but other hepatocyte organelles showed no consistent ultrastructural injury. Findings in murine sepsis paralleled those of patients, with 7.2±1.9 vs 38.7±3.9 lysosomal autophagolysosomal structures in sham and septic mice, respectively (P 0.002). Quantitative RT-PCR demonstrated that sepsis induced the upregulation of select apoptosis and cytokine gene expression with minimal changes in the core autophagy genes in liver. In conclusion, hepatocyte autophagic vacuolization increases during sepsis and is associated with mitochondrial injury. However, it is not possible to determine whether the increase in autophagic vacuolization is an adaptive response or a harbinger of cell death.
AB - Autophagy is the regulated process cells use to recycle nonessential, redundant, or inefficient components and is an adaptive response during times of stress. In addition to its function in enabling the cell to gain vital nutrients in times of stress, autophagy can also be involved in elimination of intracellular microorganisms, tumor suppression, and antigen presentation. Because of difficulty in diagnosing autophagy, few clinical studies have been performed. This study examined whether autophagy occurs in hepatocytes during sepsis. Electron microscopy (EM) was performed on liver samples obtained from both an observational clinical cohort of six septic patients and four control patients as well as liver specimens from mice with surgical sepsis (by cecal ligation and puncture) or sham operation. EM demonstrated increased autophagic vacuoles in septic vs nonseptic patients. Randomly selected fields (3000μm2) from control and septic patients contained 1.2±1.5 vs 5.3±3.3 (mean±s.d.) complex lysosomal autophagolysosomal structures per image respectively (P0.001). In rare instances, hepatocytes with autophagic vacuoles appeared to be unequivocally committed to death. Membrane alterations (membrane vacuoles, invagination into adjacent organelles, and myelin figure-like changes) occur in a subpopulation of mitochondria in sepsis, but other hepatocyte organelles showed no consistent ultrastructural injury. Findings in murine sepsis paralleled those of patients, with 7.2±1.9 vs 38.7±3.9 lysosomal autophagolysosomal structures in sham and septic mice, respectively (P 0.002). Quantitative RT-PCR demonstrated that sepsis induced the upregulation of select apoptosis and cytokine gene expression with minimal changes in the core autophagy genes in liver. In conclusion, hepatocyte autophagic vacuolization increases during sepsis and is associated with mitochondrial injury. However, it is not possible to determine whether the increase in autophagic vacuolization is an adaptive response or a harbinger of cell death.
KW - Cell death
KW - Cytokines
KW - Electron microscopy
KW - Gene expression
KW - Inflammation
UR - http://www.scopus.com/inward/record.url?scp=65649151403&partnerID=8YFLogxK
U2 - 10.1038/labinvest.2009.8
DO - 10.1038/labinvest.2009.8
M3 - Article
C2 - 19188912
AN - SCOPUS:65649151403
SN - 0023-6837
VL - 89
SP - 549
EP - 561
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 5
ER -