Concurrent inflammation as a determinant of susceptibility to toxicity from xenobiotic agents

doi:10.1016/S0300-483X(01)00523-6

Toxicology

Volume 169, Issue 3, 28 December 2001, Pages 195-208

https://doi.org/10.1016/S0300-483X(01)00523-6 Get rights and content

Abstract

Sensitivity to the toxic effects of xenobiotic agents is influenced by a number of factors. Recent evidence derived from studies using experimental animals suggests that inflammation is one of these factors. For example, induction of inflammation by coexposure to bacterial endotoxin, vitamin A or Corynebacterium parvum increases injury in response to a number of xenobiotic agents that target liver. These agents are diverse in chemical nature and in mechanism of hepatotoxic action. Factors critical to the augmentation of liver injury by inflammation include Kupffer cells, neutrophils, cytokines such as tumor necrosis factor-alpha (TNF-α) and lipid mediators such as prostaglandins, but these may vary depending on the xenobiotic agent and the mechanisms by which it alters hepatocellular homeostasis. In addition, the timing of inflammagen exposure can qualitatively alter the toxic response to chemicals. Inflammation-induced increases in susceptibility to toxicity are not limited to liver. Concurrent inflammation also sensitizes animals to the toxic effects of agents that damage the respiratory tract, kidney and lymphoid tissue. It is concluded that inflammation should be considered as a determinant of susceptibility to intoxication by xenobiotic exposure.

Introduction

There are numerous factors that can contribute to differences among individuals in their sensitivity to xenobiotic agents. These include variations in age, gender, xenobiotic metabolism, immunologic responses, reserve and repair capacity of tissues, xenobiotic absorption, coexisting disease, coexposure to additional xenobiotic agents and nutritional status, as well as underlying inflammation. Several of these determinants of sensitivity are likely to coexist and exert influences in concert in any individual. Moreover, both genetic and environmental factors have the potential to exert important influences on most of these determinants. Emerging evidence suggests that coexisting inflammation can markedly enhance toxic responses and may be an important determinant of individual susceptibility. The following is a brief review of data supporting this hypothesis.

Section snippets

Inflammation is commonplace

Humans experience episodes that expose one or more organs to factors that cause inflammation. The most obvious causal agents are bacteria and viruses, exposure to which usually precipitates inflammation as a host response aimed at eliminating pathogens. In addition, specific immune reactions against antigens typically culminate in an acute or chronic inflammatory response. Moreover, there are many disease conditions that are associated with tissue inflammation, such as arthritis, hepatitis,

Inflammation and sensitivity to xenobiotic agents

Reports in people of the relationship between coexisting inflammation and toxic responses to xenobiotic agents are lacking. This may be due in part to difficulties in timing of assessment of inflammation in patients at risk or to a lack of awareness of the influence of inflammation on responses to xenobiotics. Nevertheless, studies in experimental animals indicate that modest inflammation can heighten the sensitivity of individuals to the toxic effects of a wide variety of xenobiotic agents and

Timing of inflammation relative to xenobiotic exposure may determine the nature of the response

The temporal relationship between the occurrence of inflammation and exposure to a xenobiotic agent is likely to be an important determinant in whether a toxic response is augmented. The reason for this is that initial proinflammatory events are eventually counteracted by downregulatory mediators such as prostaglandin E₂ and interleukin-10. This results in the subsequent development of tolerance to the effects of LPS and other inflammagens. Such tolerance reduces the ability of cells to produce

Initial hypotheses

Much remains unknown about how LPS and other inflammagens exacerbate toxic responses. In 1975, Nolan suggested three mechanisms by which LPS might influence hepatotoxic responses (Nolan, 1975). One hypothesis was that liver injury induced by chemical exposure leads to decreased removal and detoxification of LPS and, therefore, greater tissue exposure (Table 2). An argument against this hypothesis is that inhibition of Kupffer cell function, which diminishes LPS clearance (Mimura et al., 1995),

Conclusion

In summary, systemic exposure to inflammagens such as LPS appears to be commonplace in people, and the magnitude of episodic exposures can be influenced by a variety of conditions. Studies in animals indicate that exposure to agents that induce inflammation markedly enhances the toxic effects of a wide variety of xenobiotic agents (Table 1). These observations suggest that concurrent inflammation should be considered as a potentially important determinant of susceptibility to intoxication from

Acknowledgements

The authors gratefully acknowledge the National Institute for Environmental Health Sciences for support of their work discussed in this paper (Grants ES04139 and ES08789).

References (107)

Y. Adachi et al.
Antibiotics prevent liver injury in rats following long-term exposure to ethanol
Gastroenterology
(1995)
D.A. Badger et al.
The role of inflammatory cells and cytochrome P450 in the potentiation of CCl₄-induced liver injury by a single dose of retinol
Toxicol. Appl. Pharmacol.
(1996)
C.C. Barton et al.
Endotoxin potentiates aflatoxin B1 hepatotoxicity in rats by a mechanism that depends on tumor necrosis factor alpha
Hepatology
(2001)
C. Bode et al.
Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess
J. Hepatol.
(1987)
W. Chamulitrat et al.
Tumor necrosis factor-alpha and nitric oxide production in endotoxin-primed rats administered carbon tetrachloride
Life Sci.
(1995)
H.Y. Cho et al.
Effects of pre-existing rhinitis on ozone-induced mucous cell metaplasia in rat nasal epithelium
Toxicol. Appl. Pharmacol.
(1999)
A.E. elSisi et al.
Vitamin A potentiation of carbon tetrachloride hepatotoxicity: role of liver macrophages and active oxygen species
Toxicol. Appl. Pharmacol.
(1993)
N. Enomoto et al.
Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin
Gastroenterology
(1998)
M.V. Fanucchi et al.
Endotoxin potentiates ozone-induced mucous cell metaplasia in rat nasal epithelium
Toxicol. Appl. Pharmacol.
(1998)
P.E. Ganey et al.
Involvement of cyclooxygenase-2 in the potentiation of allyl alcohol-induced liver injury by bacterial lipopolysaccharide
Toxicol. Appl. Pharmacol.
(2001)

U. Heemann et al.

Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury: possible connection to an interleukin-6-dependent pathway

Am. J. Pathol.

(2000)

B. Henderson et al.

Microbial/host interactions in health and disease: who controls the cytokine network?

Immunopharmacology

(1996)

A.I. Jacob et al.

Endotoxin and bacteria in portal blood

Gastroenterology

(1977)

H. Jaeschke et al.

Mechanisms of inflammatory liver injury: adhesion molecules and cytotoxicity of neutrophils

Toxicol. Appl. Pharmacol.

(1996)

D.L. Laskin et al.

Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen

Hepatology

(1995)

J.A. Lawson et al.

Pathophysiologic importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in mice

Hepatology

(2000)

J. Liu et al.

Endotoxin pretreatment protects against the hepatotoxicity of acetaminophen and carbon tetrachloride: role of cytochrome P450 suppression

Toxicology

(2000)

M.I. Luster et al.

Role of inflammation in chemical-induced hepatotoxicity

Toxicol. Lett.

(2001)

Y. Mimura et al.

Role of hepatocytes in direct clearance of lipopolysaccharide in rats

Gastroenterology

(1995)

J.P. Nolan

Progress in hepatology: the role of endotoxin in liver injury

Gastroenterology

(1975)

D.L. Peavy et al.

Toxicologic interactions between ozone and bacterial endotoxin

Environ. Res.

(1987)

R.D. Peterson et al.

Endotoxin activity of house dust extracts

J. Allergy

(1964)

D.S. Raiford et al.

Kupffer cell stimulation with Corynebacterium parvum reduces some cytochrome P450-dependent activities and diminishes acetaminophen and carbon tetrachloride-induced liver injury in the rat

Toxicol. Appl. Pharmacol.

(1994)

P. Ridker et al.

Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements

Gastroenterology

(1985)

R.K. Ross et al.

Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma

Lancet

(1992)

R.A. Roth et al.

Is exposure to bacterial endotoxin a determinant of susceptibility to intoxication from xenobiotic agents?

Toxicol. Appl. Pharmacol.

(1997)

W.K. Rumbeiha et al.

Potentiation of mercury-induced nephrotoxicity by endotoxin in the Sprague–Dawley rat

Toxicology

(2000)

W.K. Rumbeiha et al.

Augmentation of mercury-induced nephrotoxicity by endotoxin in the mouse

Toxicology

(2000)

J.M. Sauer et al.

Modulation of chemical-induced lung and liver toxicity by all- trans-retinol in the male Sprague–Dawley rat

Toxicology

(1995)

R.A. Sneed et al.

Bacterial endotoxin enhances the hepatotoxicty of allyl alcohol

Toxicol. Appl. Pharmacol.

(1997)

E. Abraham

NF-kappaB activation

Crit. Care Med.

(2000)

Y. Adachi et al.

Inactivation of Kupffer cells prevents early alcohol-induced liver injury

Hepatology

(1994)

S. Bahrami et al.

Similar cytokine but different coagulation responses to lipopolysaccharide injection in d-galactosamine-sensitized versus nonsensitized rats

Infect. Immun.

(1994)

C.C. Barton et al.

Lipopolysaccharide augments aflatoxin B(1)-induced liver injury through neutrophil-dependent and -independent mechanisms

Toxicol. Sci.

(2000)

C.C. Barton et al.

Bacterial lipopolysaccharide exposure augments aflatoxin B(1)-induced liver injury

Toxicol. Sci.

(2000)

D. Berger et al.

Time-scale of interleukin-6, myeloid related proteins (MRP), C reactive protein (CRP), and endotoxin plasma levels during the postoperative acute phase reaction

Shock

(1997)

M.E. Blazka et al.

Acetaminophen-induced hepatotoxicity is associated with early changes in NF-κB and NF-IL6 DNA binding activity

J. Inflamm.

(1995-96)

J.G. Brock-Utne et al.

Endotoxaemia in exhausted runners after a long-distance race

S. Afr. Med. J.

(1988)

A.P. Brown et al.

Lipopolysaccharide-induced hepatic injury is enhanced by polychlorinated biphenyls

Environ. Health Perspect.

(1996)

R. Burrell

Human responses to bacterial endotoxin

Circ. Shock

(1994)

G. Calcamuggi et al.

Endotoxin tolerance and polymyxin B modify liver damage and cholestasis induced by a single dose of α-naphthylisothiocyanate in the rat

Arch. Toxicol.

(1992)

T.A. Cebula et al.

Toxic interactions of benzyl alcohol with bacterial endotoxin

Infect. Immun.

(1984)

T.C. Chao et al.

An outbreak of aflatoxicosis and boric acid poisoning in Malaysia: a clinicopathological study

J. Pathol.

(1991)

H.Y. Cho et al.

Neutrophil-dependent and neutrophil-independent alterations in the nasal epithelium of ozone-exposed rats

Am. J. Respir. Crit. Care Med.

(2000)

J.G. Chosay et al.

Neutrophil margination and extravasation in sinusoids and venules of liver during endotoxin-induced injury

Am. J. Physiol.

(1997)

J.W. Christman et al.

Nuclear factor kappa B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy

Intensive Care Med.

(1998)

M.J. Czaja et al.

Lipopolysaccharide-neutralizing antibody reduces hepatocyte injury from acute hepatotoxin administration

Hepatology

(1994)

E.A. Deitch

Microbial gastrointestinal translocation

L.D. DeLeve et al.

Characterization of a reproducible rat model of hepatic veno-occlusive disease

Hepatology

(1999)

J.A. Dosman et al.

Chronic bronchitis and decreased forced expiratory flow rates in lifetime nonsmoking grain workers

Am. Rev. Respir. Dis.

(1980)

Cited by (83)

The potential role of febrile condition in reversing the hepatoprotective effects of quercetin in the livers of LPS-presensitized mice
2022, Life Sciences
Citation Excerpt :
These findings added support to the notion that QUR has been of imposing synergistic inflammatory- and pro-oxidant burden to LPS effect in the co-exposured mice. It is hypothesized that the release of inflammatory mediators might alter the hepatic tissue homeostasis, maximizing the susceptibility of the liver to chemical-induced injury [41]. In other words; the presence of LPS is considered as a predisposing factor that mediates the liver toxicity of QUR, which does not exist in the absence of LPS.
Consumption of nutraceuticals without enough data regarding their interactions has raised safety concerns. Importantly, consumption of some natural-products in health-compromised conditions has caused liver injury due to the evolved pro-oxidant load. This study evaluates the safety of quercetin (QUR), as an extensively-used flavonoid owing to its antioxidant and hepatoprotective activities, in normal- and lipopolysaccharides (LPS)-primed livers, and to investigate the influence of the LPS-induced mild inflammatory/febrile condition on QUR effects.
For liver priming, a non-injurious LPS dose that mediates limited inflammation/mild fever was chosen. Selection of QUR dose/duration of treatment, for a coherent combination-regimen, was also adopted. Single LPS i.p injection (1.5 mg/kg)/oral QUR (20 mg/kg/day, IG) for 5-days was the optimal regimen for the combination group. On day-6, serum ALT/AST/ALP levels were measured, as liver-damage biomarkers. Hepatic; MDA/GSH were determined, as oxidative-stress measures, Bcl-2/cleaved-caspase-3 were assessed as apoptosis biomarkers, IL-6 expression/NF-κB/Nrf-2 immunoreactivities were evaluated as regulators for inflammation.
Exaggerated hepatic injury was seen upon QUR treatment in LPS-presensitized mice; as evidenced by liver histopathological degeneration, which was confirmed by biochemical elevations of serum AST/ALT/ALP, along with oxidant-burden increase (↑MDA/↓GSH) and molecular augmentation of inflammation (NF-κB/IL-6 activation) that led to enhancement of proapoptotic signaling (caspase-3 activation/Bcl-2 inhibition). Such events were accompanied by potentiation of endogenous anti-inflammatory/antioxidant response (↑ hepatic Nrf-2).
The study highlights caution when QUR is consumed in health-compromised conditions, by revealing the role of fever/mild inflammation in enhancing liver toxicity upon QUR utilization, which was not apparent with moderate consumption of QUR-alone.
Virucidal, bactericidal, and sporicidal multilevel antimicrobial HEPA-ClO<inf>2</inf> filter for air disinfection in a palliative care facility
2022, Chemical Engineering Journal
Pathogenic microbes in the air are the leading cause of respiratory diseases and illnesses, and respiratory viruses are responsible for some of the world’s most devastating epidemics and pandemics. Therefore, their capture, removal, and disinfection are essential in preventing the spread of diseases. A multilevel antimicrobial HEPA-ClO₂ prepared by coating micro-encapsulated chlorine dioxide on high-efficiency particulate air (HEPA-H13) filter, displays broad-spectrum virucidal and bactericidal, as well as sporicidal activities through the combined “contact-killing” and “release-killing” properties. In-vitro cytotoxicity (i.e., human A549 cells) and in-vivo inhalation toxicity tests (i.e., Kunming mice) indicate HEPA-ClO₂ has low inhalation toxicity and is safe. Furthermore, it has superb performance against a panel of infectious respiratory viruses (e.g., influenza viruses, EV-71) and bacteria (e.g., L. pneumophila, K. pneumonia) and drug-resistant organisms (e.g., MRSA, MRPA), attaining log 2 reduction (99%) within a minute. However, spores required 30 min to reach 99% inactivation. A 260-day field trial study at a palliative care facility demonstrated that air purifiers could significantly decrease airborne particulates and microbes (bacteria and mold/fungi) and confirmed the long-term efficacy of the HEPA-ClO₂ filters and their superiority over uncoated HEPA-H13 against microbes. The experimental results from the wardroom were validated by a computational fluid dynamics (CFD) simulation.
Lipopolysaccharide (LPS)-mediated priming of toll-like receptor 4 enhances oxidant-induced prostaglandin E<inf>2</inf> biosynthesis in primary murine macrophages
2018, International Immunopharmacology
Citation Excerpt :
The in vitro results presented here have demonstrated that oxidants can activate the gene expression of COX-2 resulting in enhanced production of PGE2 in pM derived from TLR4-WT mice sensitized with LPS. Our findings confirmed in vivo studies, which revealed that LPS pre-treatment sensitized animal to xenobiotic chemical-induced cytokines storm [39]. Our results indicate that episodic exposure to LPS and other TLR4 agonists might induce a state of enhanced sensitivity to oxidants in a host, ultimately leading to pro-inflammatory responses or heightened proinflammatory phenotype that is primed for disease initiation, propagation and maintenance.
Agonists and pseudo-agonists for toll-like receptor 4 (TLR4) are common in our environment. Thus, human exposure to these agents may result in “priming or sensitization” of TLR4. A body of evidence suggests that LPS-mediated sensitization of TLR4 can increase the magnitude of responses to exogenous agents in multiple tissues. We have previously shown that reactive oxygen and nitrogen species (RONS) stimulate TLR4. There is no evidence that LPS-primed TLR4 can influence the magnitude of responses to oxidants from either endogenous or exogenous sources. In the present study, we directly tested the hypothesis that LPS-primed TLR4 will sensitize primary murine peritoneal macrophages (pM) to oxidant-mediated prostaglandin E2 (PGE₂) production. We used potassium peroxychromate (PPC) and potassium peroxynitrite (PPN) as direct in vitro sources of exogenous RONS. Our results showed that a direct treatment with PPC or PPN alone as sources of exogenous oxidants had a limited effect on PGE₂ biosynthesis. In contrast, pM sensitized by prior incubation with LPS-EK, a TLR4-specific agonist, followed by oxidant stimulation exhibited increased transcriptional and translational expression of cyclooxygenase-2 (COX-2) with enhanced PGE₂ biosynthesis/production only in pM derived from TLR4-WT mice but not in TLR4-KO mice. Thus, we have shown a critical role for LPS-primed TLR4 in oxidant-induced inflammatory phenotypes that have the potential to initiate, propagate and maintain many human diseases.
Evaluation of a human in vitro hepatocyte-NPC co-culture model for the prediction of idiosyncratic drug-induced liver injury: A pilot study
2017, Toxicology Reports
Citation Excerpt :
Exposure concentrations used by other working groups were in the range of 50–500 μM for TGZ [25,56–58], 100–800 μM for TVX [59,22,26], 250–450 μM for DcL [60,61,23,20] and >20–75 μM for KC [62,23]. Generally, there are two assumptions related to the inflammatory stress hypothesis: (1) A drug-only hepatotoxicity could be enhanced by a secondary response of immune cells (resulting in inflammation) or (2) a drug could increase an otherwise harmless (already existing) inflammatory stress that hereupon results in liver damage [46,17]. The first trigger requires the release of DAMPs by the hepatocytes, which in turn affect the immune cell behavior.
Interactions between hepatocytes and immune cells as well as inflammatory episodes are frequently discussed to play a critical role in the alteration of the individual susceptibility to idiosyncratic drug-induced liver injury (iDILI). To evaluate this hypothesis and to face the urgent need for predictive in vitro models, we established two co-culture systems based on two human cell lines in presence or absence of pro-inflammatory factors (LPS, TNF), i.e. hepatoma HepG2 cells co-cultured with monocytic or macrophage-like THP-1 cells. HepG2 monocultures served as control scenario. Mono- or co-cultures were treated with iDILI reference substances (Troglitazone [TGZ], Trovafloxacin [TVX], Diclofenac [DcL], Ketoconazole [KC]) or their non-iDILI partner compounds (Rosiglitazone, Levofloxacin, Acetylsalicylic Acid, Fluconazole). The liver cell viability was subsequently determined via WST-Assay. An enhanced cytotoxicity (synergy) or a hormetic response compared to the drug effect in the HepG2 monoculture was considered as iDILI positive. TGZ synergized in co-cultures with monocytes without an additional pro-inflammatory stimulus, while DcL and KC showed a hormetic response. All iDILI drugs synergized with TNF in the simple HepG2 monoculture, indicating its relevance as an initiator of iDILI. KC showed a synergy when co-exposed to both, monocytes and LPS, while TVX and DcL showed a synergy under the same conditions with macrophages. All described iDILI responses were not observed with the corresponding non-iDILI partner compounds. Our first results confirm that an inflammatory environment increases the sensitivity of liver cells towards iDILI compounds and point to an involvement of pro-inflammatory factors, especially TNF, in the development of iDILI.
The effect of lipopolysaccharide on liver homeostasis and diseases based on the mutual interaction of macrophages, autophagy, and damage-associated molecular patterns in male F344/DuCrlCrlj rats
2023, Veterinary Pathology
Inflammation and necrosis syndrome is associated with alterations in blood and metabolism in pigs
2022, BMC Veterinary Research

View all citing articles on Scopus

View full text

Concurrent inflammation as a determinant of susceptibility to toxicity from xenobiotic agents

Abstract

Introduction

Section snippets

Inflammation is commonplace

Inflammation and sensitivity to xenobiotic agents

Timing of inflammation relative to xenobiotic exposure may determine the nature of the response

Initial hypotheses

Conclusion

Acknowledgements

Gastroenterology

Toxicol. Appl. Pharmacol.

Hepatology

J. Hepatol.

Life Sci.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Gastroenterology

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Am. J. Pathol.

Immunopharmacology

Gastroenterology

Toxicol. Appl. Pharmacol.

Hepatology

Hepatology

Toxicology

Toxicol. Lett.

Gastroenterology

Gastroenterology

Environ. Res.

J. Allergy

Toxicol. Appl. Pharmacol.

Gastroenterology

Lancet

Toxicol. Appl. Pharmacol.

Toxicology

Toxicology

Toxicology

Toxicol. Appl. Pharmacol.

NF-kappaB activation

Crit. Care Med.

Inactivation of Kupffer cells prevents early alcohol-induced liver injury

Hepatology

Similar cytokine but different coagulation responses to lipopolysaccharide injection in d-galactosamine-sensitized versus nonsensitized rats

Infect. Immun.

Lipopolysaccharide augments aflatoxin B(1)-induced liver injury through neutrophil-dependent and -independent mechanisms

Toxicol. Sci.

Bacterial lipopolysaccharide exposure augments aflatoxin B(1)-induced liver injury

Toxicol. Sci.

Time-scale of interleukin-6, myeloid related proteins (MRP), C reactive protein (CRP), and endotoxin plasma levels during the postoperative acute phase reaction

Shock

Acetaminophen-induced hepatotoxicity is associated with early changes in NF-κB and NF-IL6 DNA binding activity

J. Inflamm.

Endotoxaemia in exhausted runners after a long-distance race

S. Afr. Med. J.

Lipopolysaccharide-induced hepatic injury is enhanced by polychlorinated biphenyls

Environ. Health Perspect.

Human responses to bacterial endotoxin

Circ. Shock

Endotoxin tolerance and polymyxin B modify liver damage and cholestasis induced by a single dose of α-naphthylisothiocyanate in the rat

Arch. Toxicol.

Toxic interactions of benzyl alcohol with bacterial endotoxin

Infect. Immun.

An outbreak of aflatoxicosis and boric acid poisoning in Malaysia: a clinicopathological study

J. Pathol.

Neutrophil-dependent and neutrophil-independent alterations in the nasal epithelium of ozone-exposed rats

Am. J. Respir. Crit. Care Med.

Neutrophil margination and extravasation in sinusoids and venules of liver during endotoxin-induced injury

Am. J. Physiol.

Nuclear factor kappa B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy

Intensive Care Med.

Lipopolysaccharide-neutralizing antibody reduces hepatocyte injury from acute hepatotoxin administration

Hepatology

Microbial gastrointestinal translocation

Characterization of a reproducible rat model of hepatic veno-occlusive disease

Hepatology

Chronic bronchitis and decreased forced expiratory flow rates in lifetime nonsmoking grain workers

Am. Rev. Respir. Dis.