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Tobacco Smoke-Induced Hepatic Injury with Steatosis, Inflammation, and Impairments in Insulin and Insulin-Like Growth Factor Signaling

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ABSTRACT

Background: Alcoholic liver disease (ALD) is associated with impairments in hepatic insulin and insulin-like growth factor (IGF) signaling through cell growth, survival, and metabolic pathways. Since not all heavy drinkers develop ALD, co-factors may be important. Epidemiologic data indicate that most heavy drinkers smoke tobacco and experimental data revealed that low-level nitrosamine exposures, including those from tobacco, can cause steatohepatitis with hepatic insulin/IGF resistance and exacerbate ALD. We hypothesize that cigarette smoke (CS) exposures also cause liver injury with impaired hepatic insulin/IGF signaling, and thereby contribute to ALD.

Methods: Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 (CS4) or 8 (CS8) weeks, or CS for 8 weeks with 2 weeks recovery (CS8+R).

Results: CS exposures caused progressive liver injury with disruption of the normal hepatic chord architecture, lobular inflammation, apoptosis or necrosis, micro-steatosis, sinusoidal dilatation, and nuclear pleomorphism. Histopathological liver injury scores increased significantly from A8 to CS4 and then further to CS8 (P<0.0001). The mean histological grade was also higher in CS8+R relative to A8 (P<0.0001) but lower than in CS4, reflecting partial resolution of injury by CS withdrawal. CS exposures impaired insulin and IGF-1 signaling through IRS-1, Akt, GSK-3β, and PRAS40. Livers from CS8+R mice had normalized or elevated levels of insulin receptor, pYpY-Insulin-R, 312S-IRS-1, 473S-Akt, S9-GSK-3β, and pT246-PRAS40 relative to A8, CS4, or CS8, reflecting partial recovery.

Conclusion: CS-mediated liver injury and steatohepatitis with impairments in insulin/IGF signalling are reminiscent of the findings in ALD. Therefore, CS exposures (either first or second-hand) may serve as a co-factor in ALD. The persistence of several abnormalities following CS exposure cessation suggests that some aspects of CS-mediated hepatic metabolic dysfunction are not readily reversible.

No MeSH data available.


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CS exposures alter hepatic architecture. Formalin-fixed, paraffin-embedded histological sections were stained with H&E to compare effects of CS exposures and withdrawal.
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Figure 1: CS exposures alter hepatic architecture. Formalin-fixed, paraffin-embedded histological sections were stained with H&E to compare effects of CS exposures and withdrawal.

Mentions: Histopathology: Formalin-fixed, paraffin-embedded H&E stained sections of livers revealed the normal uniform chord-like architecture in A8 controls. Livers from CS4 mice exhibited disruption of the normal chord-like architecture with marked variability in hepatocyte size and nuclear morphology, foci of necrosis, inflammation and cytoplasmic vacuolation, and scattered apoptotic (Councilman) bodies or hepatocytes with ballooning cytoplasmic degeneration. In CS8 livers, the hepatic chord architecture was partly restored and inflammation was milder and less aggregated compared with CS4 livers. However, the longer durations of CS exposure, including after 2 weeks recovery, resulted in hepatocellular microvesicular steatosis, which was more pronounced in the CS8+R group than CS8. Paradoxically, the CS8+R livers exhibited extreme cytoplasmic pallor, marked variability in nuclear size, small foci of inflammation, increased mitoses, and sinusoidal dilatation with congestion (Figure 1).


Tobacco Smoke-Induced Hepatic Injury with Steatosis, Inflammation, and Impairments in Insulin and Insulin-Like Growth Factor Signaling
CS exposures alter hepatic architecture. Formalin-fixed, paraffin-embedded histological sections were stained with H&E to compare effects of CS exposures and withdrawal.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979551&req=5

Figure 1: CS exposures alter hepatic architecture. Formalin-fixed, paraffin-embedded histological sections were stained with H&E to compare effects of CS exposures and withdrawal.
Mentions: Histopathology: Formalin-fixed, paraffin-embedded H&E stained sections of livers revealed the normal uniform chord-like architecture in A8 controls. Livers from CS4 mice exhibited disruption of the normal chord-like architecture with marked variability in hepatocyte size and nuclear morphology, foci of necrosis, inflammation and cytoplasmic vacuolation, and scattered apoptotic (Councilman) bodies or hepatocytes with ballooning cytoplasmic degeneration. In CS8 livers, the hepatic chord architecture was partly restored and inflammation was milder and less aggregated compared with CS4 livers. However, the longer durations of CS exposure, including after 2 weeks recovery, resulted in hepatocellular microvesicular steatosis, which was more pronounced in the CS8+R group than CS8. Paradoxically, the CS8+R livers exhibited extreme cytoplasmic pallor, marked variability in nuclear size, small foci of inflammation, increased mitoses, and sinusoidal dilatation with congestion (Figure 1).

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Alcoholic liver disease (ALD) is associated with impairments in hepatic insulin and insulin-like growth factor (IGF) signaling through cell growth, survival, and metabolic pathways. Since not all heavy drinkers develop ALD, co-factors may be important. Epidemiologic data indicate that most heavy drinkers smoke tobacco and experimental data revealed that low-level nitrosamine exposures, including those from tobacco, can cause steatohepatitis with hepatic insulin/IGF resistance and exacerbate ALD. We hypothesize that cigarette smoke (CS) exposures also cause liver injury with impaired hepatic insulin/IGF signaling, and thereby contribute to ALD.

Methods: Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 (CS4) or 8 (CS8) weeks, or CS for 8 weeks with 2 weeks recovery (CS8+R).

Results: CS exposures caused progressive liver injury with disruption of the normal hepatic chord architecture, lobular inflammation, apoptosis or necrosis, micro-steatosis, sinusoidal dilatation, and nuclear pleomorphism. Histopathological liver injury scores increased significantly from A8 to CS4 and then further to CS8 (P<0.0001). The mean histological grade was also higher in CS8+R relative to A8 (P<0.0001) but lower than in CS4, reflecting partial resolution of injury by CS withdrawal. CS exposures impaired insulin and IGF-1 signaling through IRS-1, Akt, GSK-3β, and PRAS40. Livers from CS8+R mice had normalized or elevated levels of insulin receptor, pYpY-Insulin-R, 312S-IRS-1, 473S-Akt, S9-GSK-3β, and pT246-PRAS40 relative to A8, CS4, or CS8, reflecting partial recovery.

Conclusion: CS-mediated liver injury and steatohepatitis with impairments in insulin/IGF signalling are reminiscent of the findings in ALD. Therefore, CS exposures (either first or second-hand) may serve as a co-factor in ALD. The persistence of several abnormalities following CS exposure cessation suggests that some aspects of CS-mediated hepatic metabolic dysfunction are not readily reversible.

No MeSH data available.


Related in: MedlinePlus