Effect of cigarette smoke on drug metabolism in vitro.

N-demethylation of aminopyrine and C-hydroxylation of aniline by hepatic microsomal enzymes were measured during $\text{in vitro}$ exposure to cigarette smoke. Metabolism of aminopyrine during smoke exposure was not significantly altered. Metabolism of aniline during smoke exposure was inhibited 70–80% (P < .001) thus indicating that an initial effect of exposure to cigarette smoke is a decreased rate of biotransformation via C-hydroxylation. This finding, coupled with the findings of other investigators who have shown that the delayed effect of exposure to cigarette smoke is induction of hydroxylase activity, suggests that cigarette smoke produces a biphasic alteration in certain hepatic biotransformation processes.     

Influenza Virus-Induced Lung Inflammation Was Modulated by Cigarette Smoke Exposure in Mice

Although smokers have increased susceptibility and severity of seasonal influenza virus infection, there is no report about the risk of 2009 pandemic H1N1 (pdmH1N1) or avian H9N2 (H9N2/G1) virus infection in smokers. In our study, we used mouse model to investigate the effect of cigarette smoke on pdmH1N1 or H9N2 virus infection. Mice were exposed to cigarette smoke for 21 days and then infected with pdmH1N1 or H9N2 virus. Control mice were exposed to air in parallel. We found that cigarette smoke exposure alone significantly upregulated the lung inflammation. Such prior cigarette smoke exposure significantly reduced the disease severity of subsequent pdmH1N1 or H9N2 virus infection. For pdmH1N1 infection, cigarette smoke exposed mice had significantly lower mortality than the control mice, possibly due to the significantly decreased production of inflammatory cytokines and chemokines. Similarly, after H9N2 infection, cigarette smoke exposed mice displayed significantly less weight loss, which might be attributed to lower cytokines and chemokines production, less macrophages, neutrophils, CD4⁺ and CD8⁺ T cells infiltration and reduced lung damage compared to the control mice. To further investigate the underlying mechanism, we used nicotine to mimic the effect of cigarette smoke both in vitro and in vivo. Pre-treating the primary human macrophages with nicotine for 72 h significantly decreased their expression of cytokines and chemokines after pdmH1N1 or H9N2 infection. The mice subcutaneously and continuously treated with nicotine displayed significantly less weight loss and lower inflammatory response than the control mice upon pdmH1N1 or H9N2 infection. Moreover, α7 nicotinic acetylcholine receptor knockout mice had more body weight loss than wild-type mice after cigarette smoke exposure and H9N2 infection. Our study provided the first evidence that the pathogenicity of both pdmH1N1 and H9N2 viruses was alleviated in cigarette smoke exposed mice, which might partially be attributed to the immunosuppressive effect of nicotine.     

Abnormal spatial diffusion of Ca2+ in F508del-CFTR airway epithelial cells

Background

Cigarette smoke has both pro-inflammatory and immunosuppressive effects. Both active and passive cigarette smoke exposure are linked to an increased incidence and severity of respiratory virus infections, but underlying mechanisms are not well defined. We hypothesized, based on prior gene expression profiling studies, that upregulation of pro-inflammatory mediators by short term smoke exposure would be protective against a subsequent influenza infection.

Methods

BALB/c mice were subjected to whole body smoke exposure with 9 cigarettes/day for 4 days. Mice were then infected with influenza A (H3N1, Mem71 strain), and analyzed 3 and 10 days later (d3, d10). These time points are the peak and resolution (respectively) of influenza infection.

Results

Inflammatory cell influx into the bronchoalveolar lavage (BALF), inflammatory mediators, proteases, histopathology, viral titres and T lymphocyte profiles were analyzed. Compared to smoke or influenza alone, mice exposed to smoke and then influenza had more macrophages, neutrophils and total lymphocytes in BALF at d3, more macrophages in BALF at d10, lower net gelatinase activity and increased activity of tissue inhibitor of metalloprotease-1 in BALF at d3, altered profiles of key cytokines and CD4+ and CD8+ T lymphocytes, worse lung pathology and more virus-specific, activated CD8+ T lymphocytes in BALF. Mice smoke exposed before influenza infection had close to 10-fold higher lung virus titres at d3 than influenza alone mice, although all mice had cleared virus by d10, regardless of smoke exposure. Smoke exposure caused temporary weight loss and when smoking ceased after viral infection, smoke and influenza mice regained significantly less weight than smoke alone mice.

Conclusion

Smoke induced inflammation does not protect against influenza infection. In most respects, smoke exposure worsened the host response to influenza. This animal model may be useful in studying how smoke worsens respiratory viral infections.     

Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice

Background

Cigarette smoke has both pro-inflammatory and immunosuppressive effects. Both active and passive cigarette smoke exposure are linked to an increased incidence and severity of respiratory virus infections, but underlying mechanisms are not well defined. We hypothesized, based on prior gene expression profiling studies, that upregulation of pro-inflammatory mediators by short term smoke exposure would be protective against a subsequent influenza infection.

Methods

BALB/c mice were subjected to whole body smoke exposure with 9 cigarettes/day for 4 days. Mice were then infected with influenza A (H3N1, Mem71 strain), and analyzed 3 and 10 days later (d3, d10). These time points are the peak and resolution (respectively) of influenza infection.

Results

Inflammatory cell influx into the bronchoalveolar lavage (BALF), inflammatory mediators, proteases, histopathology, viral titres and T lymphocyte profiles were analyzed. Compared to smoke or influenza alone, mice exposed to smoke and then influenza had more macrophages, neutrophils and total lymphocytes in BALF at d3, more macrophages in BALF at d10, lower net gelatinase activity and increased activity of tissue inhibitor of metalloprotease-1 in BALF at d3, altered profiles of key cytokines and CD4+ and CD8+ T lymphocytes, worse lung pathology and more virus-specific, activated CD8+ T lymphocytes in BALF. Mice smoke exposed before influenza infection had close to 10-fold higher lung virus titres at d3 than influenza alone mice, although all mice had cleared virus by d10, regardless of smoke exposure. Smoke exposure caused temporary weight loss and when smoking ceased after viral infection, smoke and influenza mice regained significantly less weight than smoke alone mice.

Conclusion

Smoke induced inflammation does not protect against influenza infection.In most respects, smoke exposure worsened the host response to influenza. This animal model may be useful in studying how smoke worsens respiratory viral infections.     

Role of Nrf2 in host defense against influenza virus in cigarette smoke-exposed mice

Influenza virus is a common respiratory tract viral infection. Although influenza can be fatal in patients with chronic pulmonary diseases such as chronic obstructive pulmonary disease, its pathogenesis is not fully understood. The Nrf2-mediated antioxidant system is essential to protect the lungs from oxidative injury and inflammation. In the present study, we investigated the role of Nrf2 in protection against influenza virus-induced pulmonary inflammation after cigarette smoke exposure with both in vitro and in vivo approaches. For in vitro analyses, peritoneal macrophages isolated from wild-type and Nrf2-deficient mice were treated with poly(I:C) and/or cigarette smoke extract. For in vivo analysis, these mice were infected with influenza A virus with or without exposure to cigarette smoke. In Nrf2-deficient macrophages, NF-κB activation and the induction of its target inflammatory genes were enhanced after costimulation with cigarette smoke extract and poly(I:C) compared with wild-type macrophages. The induction of antioxidant genes was observed for the lungs of wild-type mice but not those of Nrf2-deficient mice after cigarette smoke exposure. Cigarette smoke-exposed Nrf2-deficient mice showed higher rates of mortality than did wild-type mice after influenza virus infection, with enhanced peribronchial inflammation, lung permeability damage, and mucus hypersecretion. Lung oxidant levels and NF-κB-mediated inflammatory gene expression in the lungs were also enhanced in Nrf2-deficient mice. Our data indicate that the antioxidant pathway controlled by Nrf2 is pivotal for protection against the development of influenza virus-induced pulmonary inflammation and injury under oxidative conditions.     

Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection

Background

Chronic obstructive pulmonary disease is a progressive lung disease that is punctuated by periods of exacerbations (worsening of symptoms) that are attributable to viral infections. While rhinoviruses are most commonly isolated viruses during episodes of exacerbation, influenza viruses have the potential to become even more problematic with the increased likelihood of an epidemic.

Methodology and Principal Findings

This study examined the impact of current and potential pharmacological targets namely the systemic corticosteroid dexamethasone and the peroxisome proliferator-activated receptor- gamma agonist pioglitazone on the outcome of infection in smoke-exposed mice. C57BL/6 mice were exposed to room air or cigarette smoke for 4 days and subsequently inoculated with an H1N1 influenza A virus. Interventions were delivered daily during the course of infection. We show that smoke-exposed mice have an exacerbated inflammatory response following infection. While smoke exposure did not compromise viral clearance, precision cut lung slices from smoke-exposed mice showed greater expression of CC (MCP-1, -3), and CXC (KC, MIP-2, GCP-2) chemokines compared to controls when stimulated with a viral mimic or influenza A virus. While dexamethasone treatment partially attenuated the inflammatory response in the broncho-alveolar lavage of smoke-exposed, virally-infected animals, viral-induced neutrophilia was steroid insensitive. In contrast to controls, dexamethasone-treated smoke-exposed influenza-infected mice had a worsened health status. Pioglitazone treatment of virally-infected smoke-exposed mice proved more efficacious than the steroid intervention. Further mechanistic evaluation revealed that a deficiency in CCR2 did not improve the inflammatory outcome in smoke-exposed, virally-infected animals.

Conclusions and Significance

This animal model of cigarette smoke and H1N1 influenza infection demonstrates that smoke-exposed animals are differentially primed to respond to viral insult. While providing a platform to test pharmacological interventions, this model demonstrates that treating viral exacerbations with alternative anti-inflammatory drugs, such as PPAR-gamma agonists should be further explored since they showed greater efficacy than systemic corticosteroids.     

Pulmonary cell response to bacterial challenge in mutant mice with some hereditary alterations resembling cystic fibrosis

Animal models make it possible to perform studies that normally can not be done in human beings. In the present work, the cellular response pattern of the lungs both to the environment and to a challenger strain of bacteria were analyzed in two mouse mutations-cribriform degeneration ($\text{cri}$) and motheaten (me)-. The mice were submitted to an infective aerosol containing $\text{Staphylococcus aureus}$ and were killed either immediately or 4 h after exposure; pulmonary washings were performed in these animals as well as in non-infected controls. The results showed neither quantitative differences in the total cell count nor in cell viability between the different groups. However, there were qualitative changes in the differential cell content characterized by a neutrophilic response in $\text{cri}$/$\text{cri}$ mice and a giant cell response in $\text{me}$/$\text{me}$ mice. Since most of the cystic fibrosis patients suffer from chronic lung infection, with a persistently high proportion of neutrophils, these findings point to the $\text{cri}$/$\text{cri}$ mouse as a promising animal model for cystic fibrosis studies.     

Impairment of primary in vitro response of New Zealand mouse spleen cells to a thymic-dependent antigen.

New Zealand Black (NZB) and NZB by New Zealand White (NZW) F₁ hybrid ($\text{B}\text{W}$) mice develop clinical signs of autoimmune disease between 6 and 10 months of age but spleen cells from these strains have a greatly reduced in vitro response to sheep erythrocytes (SRBC) as early as 5–6 weeks of age. This hyporesponsiveness can be only partially restored with 2-mercaptoethanol, allogeneic macrophages or spleen cells, or allogeneic factor. The response of NZB and $\text{B}\text{W}$ spleen cells to the thymic independent antigen DNP-Ficoll is nearly normal. The reduced in vitro SRBC response was found to be attributable to splenic T and B cells rather than macrophages. Macrophages from NZB mice were found to function normally. The in vitro behavior of NZB lymphocytes is very similar to non-autoimmune mice infected with common murine viral pathogens. NZB and $\text{B}\text{W}$ mice may be making an active immune response as early as 5 weeks of age.     

In vitro production of immune interferon by spleen cells of mice immunized with herpes simplex virus.

In Vitro production of Immune Interferon (IF) in response to Herpes Simplex Virus (HSV) antigen by sensitized spleen cells from C57B1/6 (B6) mice could be detected as early as 3 and for at least 20 days after ip infection of HSV. Maximal levels of IF were produced after 10 hr of culture, but there was no decay of activity when supernatants were sampled during the subsequent 3 days. The IF produced shared certain known properties of immune IF and was not neutralized by an antiserum against viral-induced (type I) IF. DBA/2 (D2) mice which are considerably more sensitive in vivo to HSV infection than B6 mice produced significantly lower amounts of immune IF in the in vitro test system regardless whether high or low doses of virus were injected. The same pattern of results was observed when resistant B6D2F1 hybrid mice were compared with $\text{A}\text{J}$ and Balb/c mice which are about as sensible to ip infection with HSV as DBA/2 mice in our laboratory. These results demonstrate a remarkable defect of in vitro cellular immunity in mice susceptible to a virus infection when compared with resistant mice. Conceivably, a similar defect may be of in vivo relevance.     

Trichinella spiralis: Characterization and strain distribution of rapid expulsion in inbred mice

Appropriately immunized mice display a response that is biologically equivalent to rat rapid expulsion. Only two inbred strains ($\text{NFR}\text{N}\text{and}\text{NFS}\text{N}$ derived from NIH Swiss mice) have been shown to respond in this manner. Mice of the $\text{Balb}\text{c}$, CBA, $\text{A}\text{He}$, C₃H, SJL, or C₅₇Bl strains are “nonresponders” which require approximately twice as much intestinal exposure (in days) to Trichinella spiralis to elicit a response half as effective. Genetically, the responder is dominant, autosomal, and does not appear to be linked to the MHC. The characteristics of mouse and rat rapid expulsion of T. spiralis are not identical but share these features: initial rejection within 24 hr of challenge; a rejection efficiency >90%, from 1 to 5 weeks after the primary; induction of response does not require exposure to the complete infection; rapid expulsion is immunologically specific for preadults; adult worms are resistant. While a genetic basis for responsiveness exists in mice there is, as yet, no evidence for genetic control in rats. In both mice and rats, rapid expulsion is distinguished from the intestinal hyperreactivity associated with rejection of the primary infection by the kinetics and amplitude of the rejection of transplanted adult worms.     

Imbalance in zinc homeostasis enhances lung Tissue Loss following cigarette smoke exposure

Cigarette smoke exposure is a major cause of chronic obstructive pulmonary disease. Cadmium is a leading toxic component of cigarette smoke. Cadmium and zinc are highly related metals. Whereas, zinc is an essential metal required for normal health, cadmium is highly toxic. Zrt- and Irt-like protein 8 (ZIP8) is an avid transporter of both zinc and cadmium into cells and is abundantly expressed in the lung of smokers compared to nonsmokers. Our objective was to determine whether disturbed zinc homeostasis through diet or the zinc transporter ZIP8 increase susceptibility to lung damage following prolonged cigarette smoke exposure.MethodsCigarette smoke exposure was evaluated in the lungs of mice subject to insufficient and sufficient zinc intakes, in transgenic ZIP8 overexpressing mice, and a novel myeloid-specific ZIP8 knockout strain.ResultsModerate depletion of zinc intakes in adult mice resulted in a significant increase in lung cadmium burden and permanent lung tissue loss following prolonged smoke exposure. Overexpression of ZIP8 resulted in increased lung cadmium burden and more extensive lung damage, whereas cigarette smoke exposure in ZIP8 knockout mice resulted in increased lung tissue loss without a change in lung cadmium content, but a decrease in zinc.ConclusionsOverall, findings were consistent with past human studies. Imbalance in Zn homeostasis increases susceptibility to permanent lung injury following prolonged cigarette smoke exposure. Based on animal studies, both increased and decreased ZIP8 expression enhanced irreversible tissue damage in response to prolonged tobacco smoke exposure. We believe these findings represent an important advancement in our understanding of how imbalance in zinc homeostasis and cadmium exposure via tobacco smoke may increase susceptibility to smoking-induced lung disease.     

Cigarette smoke inhibits BAFF expression and mucosal immunoglobulin A responses in the lung during influenza virus infection

Background

It is incompletely understood how cigarette smoke (CS) exposure affects lung mucosal immune responses during viral respiratory infections. B cell activating factor belonging to the tumor necrosis factor family (BAFF) plays an important role in the induction of secretory immunoglobulin A (S-IgA) which is the main effector of the mucosal immune system. We therefore investigated the effects of CS exposure on BAFF expression and S-IgA responses in the lung during influenza virus infection.

Methods

Mice were exposed to CS and/or infected with influenza virus. Bronchoalveolar lavage fluid and lung compartments were analyzed for BAFF expression, influenza-specific S-IgA level and histological changes. Lung B cells were isolated and the activation-induced cytidine deaminase (Aicda) expression was determined. BEAS-2B cells were treated with CS extract (CSE), influenza virus, interferon beta or N-acetylcysteine and BAFF expression was measured.

Results

CS inhibited BAFF expression in the lung, particularly after long-term exposure. BAFF and S-IgA levels were increased during influenza virus infection. Three-month CS exposure prior to influenza virus infection resulted in reduced BAFF and S-IgA levels in the lung as well as augmented pulmonary inflammation on day 7 after infection. Prior CS exposure also caused decreased Aicda expression in lung B cells during infection. Neutralization of BAFF in the lung resulted in reduced S-IgA levels during influenza virus infection. CSE inhibited virus-mediated BAFF induction in a dose-dependent manner in BEAS-2B cells, while this inhibition of BAFF by CSE was prevented by pretreatment with the antioxidant N-acetylcysteine.

Conclusions

Our findings indicate that CS may hinder early mucosal IgA responses in the lung during influenza virus infection through oxidative inhibition of BAFF, which might contribute to the increased incidence and severity of viral infections in smokers.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0201-y) contains supplementary material, which is available to authorized users.     

Maternal smoking and the retinoid pathway in the developing lung

Background

Maternal smoking is a risk factor for pediatric lung disease, including asthma. Animal models suggest that maternal smoking causes defective alveolarization in the offspring. Retinoic acid signaling modulates both lung development and postnatal immune function. Thus, abnormalities in this pathway could mediate maternal smoking effects. We tested whether maternal smoking disrupts retinoic acid pathway expression and functioning in a murine model.

Methods

Female C57Bl/6 mice with/without mainstream cigarette smoke exposure (3 research cigarettes a day, 5 days a week) were mated to nonsmoking males. Cigarette smoke exposure continued throughout the pregnancy and after parturition. Lung tissue from the offspring was examined by mean linear intercept analysis and by quantitative PCR. Cell culture experiments using the type II cell-like cell line, A549, tested whether lipid-soluble cigarette smoke components affected binding and activation of retinoic acid response elements in vitro.

Results

Compared to tobacco-naïve mice, juvenile mice with tobacco toxin exposure had significantly (P < 0.05) increased mean linear intercepts, consistent with an alveolarization defect. Tobacco toxin exposure significantly (P < 0.05) decreased mRNA and protein expression of retinoic acid signaling pathway elements, including retinoic acid receptor alpha and retinoic acid receptor beta, with the greatest number of changes observed between postnatal days 3–5. Lipid-soluble cigarette smoke components significantly (P < 0.05) decreased retinoic acid-induced binding and activation of the retinoic acid receptor response element in A549 cells.

Conclusions

A murine model of maternal cigarette smoking causes abnormal alveolarization in association with altered retinoic acid pathway element expression in the offspring. An in vitro cell culture model shows that lipid-soluble components of cigarette smoke decrease retinoic acid response element activation. It is feasible that disruption of retinoic acid signaling contributes to the pediatric lung dysfunction caused by maternal smoking.     

Toxoplasma gondii: lymphocyte function during acute infection in mice

T-cell function during acute Toxoplasma gondii infection was evaluated in murine models. Blastogenic response to the T-cell mitogen concanavalin A (Con A) was not depressed during infection with either the C37 or the C56 strain of T. gondii in either $\text{BALB}\text{c}$ or $\text{C}\text{57}\text{BL}\text{6}\text{J}$ mice that were inoculated either intravenously or intraperitoneally with varying doses of tachyzoites 7, 14, or 30 days earlier. In evaluation of lymphocytes from individual mice, utilization of a range of concentrations of Con A was found to be important for correct interpretation of results. There was variability in the magnitude of response of individual mice and in the concentration of mitogen that produced an optimal response among the inbred mice. The T-cell-dependent, primary antibody response to sheep red blood cells (SRBC) was not depressed in $\text{BALB}\text{c}$ mice infected with the C37 strain of Toxoplasma 1 and 8 days prior to inoculation with SRBC. A lower blastogenic reponse to Con A of lymphocytes from $\text{C}\text{57}\text{BL}\text{6}\text{J}$ mice compared with that of $\text{BALB}\text{c}$ mice appeared to correlate with increased susceptibility of $\text{C}\text{57}\text{BL}\text{6}\text{J}$ mice to low-challenge inocula of T. gondii.     

Alterations in Skeletal Muscle Cell Homeostasis in a Mouse Model of Cigarette Smoke Exposure

Background

Skeletal muscle dysfunction is common in chronic obstructive pulmonary disease (COPD), a disease mainly caused by chronic cigarette use. An important proportion of patients with COPD have decreased muscle mass, suggesting that chronic cigarette smoke exposure may interfere with skeletal muscle cellular equilibrium. Therefore, the main objective of this study was to investigate the kinetic of the effects that cigarette smoke exposure has on skeletal muscle cell signaling involved in protein homeostasis and to assess the reversibility of these effects.

Methods

A mouse model of cigarette smoke exposure was used to assess skeletal muscle changes. BALB/c mice were exposed to cigarette smoke or room air for 8 weeks, 24 weeks or 24 weeks followed by 60 days of cessation. The gastrocnemius and soleus muscles were collected and the activation state of key mediators involved in protein synthesis and degradation was assessed.

Results

Gastrocnemius and soleus were smaller in mice exposed to cigarette smoke for 8 and 24 weeks compared to room air exposed animals. Pro-degradation proteins were induced at the mRNA level after 8 and 24 weeks. Twenty-four weeks of cigarette smoke exposure induced pro-degradation proteins and reduced Akt phosphorylation and glycogen synthase kinase-3β quantity. A 60-day smoking cessation period reversed the cell signaling alterations induced by cigarette smoke exposure.

Conclusions

Repeated cigarette smoke exposure induces reversible muscle signaling alterations that are dependent on the duration of the cigarette smoke exposure. These results highlights a beneficial aspect associated with smoking cessation.     

Change of enzyme activities during the early stage of influenza virus infection

Intracellular activities of various hydrolytic enzymes were investigated in monkey kidney cells infected with the $\text{A}\text{NWS}$ strain of influenza virus. At the early stage of infection, there was a significant decrease in the activity of β-D-galactosidase, α-D-mannosidase, $\text{N}$-acetyl-β-D-glucosaminidase, acid and alkaline phosphatase. The decrease was roughly proportional to the multiplicity of infection, and restored at 2 hr after the infection. Corresponding to this intracellular decrease, there was an increase in the activities of these enzyme outside the cells. The results suggested that these hydrolytic enzymes would be released from the cell membrane or the lysosomes near the membrane in the process of adsorption and penetration of the virus particles.     

Mouse Protocadherin-1 Gene Expression Is Regulated by Cigarette Smoke Exposure In Vivo

Protocadherin-1 (PCDH1) is a novel susceptibility gene for airway hyperresponsiveness, first identified in families exposed to cigarette smoke and is expressed in bronchial epithelial cells. Here, we asked how mouse Pcdh1 expression is regulated in lung structural cells in vivo under physiological conditions, and in both short-term cigarette smoke exposure models characterized by airway inflammation and hyperresponsiveness and chronic cigarette smoke exposure models. Pcdh1 gene-structure was investigated by Rapid Amplification of cDNA Ends. Pcdh1 mRNA and protein expression was investigated by qRT-PCR, western blotting using isoform-specific antibodies. We observed 87% conservation of the Pcdh1 nucleotide sequence, and 96% conservation of the Pcdh1 protein sequence between men and mice. We identified a novel Pcdh1 isoform encoding only the intracellular signalling motifs. Cigarette smoke exposure for 4 consecutive days markedly reduced Pcdh1 mRNA expression in lung tissue (3 to 4-fold), while neutrophilia and airway hyperresponsiveness was induced. Moreover, Pcdh1 mRNA expression in lung tissue was reduced already 6 hours after an acute cigarette-smoke exposure in mice. Chronic exposure to cigarette smoke induced loss of Pcdh1 protein in lung tissue after 2 months, while Pcdh1 protein levels were no longer reduced after 9 months of cigarette smoke exposure. We conclude that Pcdh1 is highly homologous to human PCDH1, encodes two transmembrane proteins and one intracellular protein, and is regulated by cigarette smoke exposure in vivo.     

Hymenolepis microstoma: Mouse strain differences in resistance to a challenge infection

Antibody responses and host resistance to the tapeworm, Hymenolepis microstoma, were investigated using $\text{AKR}\text{J}$ and $\text{C}\text{3}\text{HeB}\text{FeJ}$ strains of mice. AKR mice were significantly more resistant than controls to a secondary infection following exposure to a 3-, 21-, or 40-day primary infection. During a primary infection, intestinal anti-worm antibody responses measured by an enzyme-linked immunosorbent assay were elevated in the more resistant AKR strain, whereas serum antibody titers did not differ between the two strains. However, during a secondary infection, serum IgA titers were higher in AKR mice than C3H mice. Suppression of the serum IgA anti-worm response by oral administration of lipopolysaccharide also suppressed resistance to a secondary infection. Intraperitoneal immunization with worm antigen resulted in a minor degree of protection in AKR mice. This protection was associated with increased intestinal antibody titers compared to mice not demonstrating protection. These results suggest that the protective responses observed in AKR mice relative to C3H mice reflect differences in mucosal antibody responses to H. microstoma.     

Hymenolepis nana: Immunogenicity of a lumen phase of the direct cycle and failure of autoinfection in BALBc mice

When $\text{BALB}\text{c}$ mice were given $\text{BALB}\text{c}$ mouse-derived cysticercoids (cysts) of Hymenolepis nana, only $\text{1}\text{43}$ mice became autoinfected, whereas most ($\text{31}\text{38}$) of dd mice given the same infection became massively autoinfected with mature worms. When $\text{BALB}\text{c}$ mice initially given cysts were challenged with eggs on Day 7, just before the patency of the primary infection, there was normal development into cysts, but almost none of them developed into adult worms. Thus, the failure of autoinfection of H. nana in $\text{BALB}\text{c}$ mice was not a result of failure of eggs to differentiate into cysts in the intestinal tissue, but a result of failure of these cysts to develop into adult worms in the lumen. The reasons why autoinfection does occur in dd and other strains of mice and not in the $\text{BALB}\text{c}$ strain are discussed in terms of the difference in onset of the late response in these strains of mice, ie., the response that is acquired after egg inoculation, and is directed against the lumen phase of cyst challenges. It is strongly suggested that (1) the lumen phase which follows cyst inoculation is highly immunogenic, but clearly differs from tissue phase which follows egg inoculation, (2) the autoinfection which occurs in some strains of mice is therefore not a result of no or poor immunogenicity of the lumen phase but is due to a delay of onset of the late response with the result that a secondary generation may mature, and (3) in other strains of mice, including $\text{BALB}\text{c}$, which acquire the late response within 15 days of initial egg inoculation, autoinfection normally does not occur after cyst infections.