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Biomedical subjects

Steven R Kleeberger

Publications and source records attributed to Steven R Kleeberger.

At least 19 recordsLinked to original sources
PubMed2006

C5 modulates airway hyperreactivity and pulmonary eosinophilia during enhanced respiratory syncytial virus disease by decreasing C3a receptor expression.

Enhanced respiratory syncytial virus disease, a serious pulmonary disorder that affected recipients of an inactivated vaccine against respiratory syncytial virus in the 1960s, has delayed the development of vaccines against the virus. The enhanced disease was characterized by immune complex-mediated airway hyperreactivity and a severe pneumonia associated with pulmonary eosinophilia. In this paper, we show that complement factors contribute to enhanced-disease phenotypes. Mice with a targeted disruption of complement component C5 affected by the enhanced disease displayed enhanced airway reactivity, lung eosinophilia, and mucus production compared to wild-type mice and C5-deficient mice reconstituted with C5. C3aR expression in bronchial epithelial and smooth muscle cells in the lungs of C5-deficient mice was enhanced compared to that in wild-type and reconstituted rodents. Treatment of C5-deficient mice with a C3aR antagonist significantly attenuated airway reactivity, eosinophilia, and mucus production. These results indicate that C5 plays a crucial role in modulating the enhanced-disease phenotype, by affecting expression of C3aR in the lungs. These findings reveal a novel autoregulatory mechanism for the complement cascade that affects the innate and adaptive immune responses.

Animals↗
PubMed2006

The impact of infection with human metapneumovirus and other respiratory viruses in young infants and children at high risk for severe pulmonary disease.

We conducted a prospective, observational study to characterize the clinical manifestations of respiratory infections caused by human metapneumovirus (hMPV) and other viruses in 194 premature infants and young children with chronic lung disease or congenital heart disease in Buenos Aires. Children had 567 episodes of respiratory illness and were monitored until they were 2 years old or until the completion of the study. hMPV elicited 12 infections (2%) year-round; 30% were of moderate or greater severity. Human parainfluenza virus type 3 caused 24 infections (4%), and 5 (25%) of 20 lung infections led to hospitalization. Respiratory syncytial virus (RSV) caused 33 episodes--17% of infections and 32% of hospitalizations during the respiratory season. None of the 10 children infected with influenza virus had severe disease. The present study of at-risk children suggests that hMPV and influenza virus are infrequent agents of severe disease and highlights the need for preventive interventions against RSV in developing countries.

Adult↗
PubMed2006

Polymorphisms in chemokine and chemokine receptor genes and the development of coal workers' pneumoconiosis.

Chemokines and their receptors are key regulators of inflammation and may participate in the lung fibrotic process. Associations of polymorphisms in CCL5 (G-403A) and its receptor CCR5 (Delta32), CCL2 (A-2578G) and CCR2 (V64I), and CX3CR1 V249I and T280M with coal worker's pneumoconiosis (CWP) were investigated in 209 miners examined in 1990, 1994 and 1999. Coal dust exposure was assessed by job history and ambient measures. The main health outcome was lung computed tomography (CT) score in 1990. Internal coherence was assessed by studying CT score in 1994, 4-year change in CT score, and CWP prevalence in 1999. CCR5 Delta32 carriers had significantly higher CT score in 1990 and 1994 (2.15 vs. 1.28, p=0.01; 3.04 vs. 1.80, p=0.04). The CX3CR1 I249 allele was significantly associated with lower 1990 CT score and lower progression in 4-year change in CT score in CCR5 Delta32 carriers only (p for interaction=0.03 and 0.02). CX3CR1 V249I was associated with lower 1999 CWP prevalence (16.7%, 13.2%, 0.0% for VV, VI and II); the effect was most evident in miners with high dust exposure (31.6%, 21.7%, 0.0%). Our findings indicate that chemokine receptors CCR5 and CX3CR1 may be involved in the development of pneumoconiosis.

Adult↗
PubMed2006

The cysteine-rich region and secreted form of the attachment G glycoprotein of respiratory syncytial virus enhance the cytotoxic T-lymphocyte response despite lacking major histocompatibility complex class I-restricted epitopes.

The cytotoxic T-lymphocyte (CTL) response is important for the control of viral replication during respiratory syncytial virus (RSV) infection. The attachment glycoprotein (G) of RSV does not encode major histocompatibility complex class I-restricted epitopes in BALB/c mice (H-2(d)). Furthermore, studies to date have described an absence of significant CTL activity directed against this protein in humans. Therefore, G previously was not considered necessary for the generation of RSV-specific CTL responses. In this study, we demonstrate that, despite lacking H-2(d)-restricted epitopes, G enhances the generation of an effective CTL response against RSV. Furthermore, we show that this stimulatory effect is independent of virus titers and RSV-induced inflammation; that it is associated primarily with the secreted form of G; and that the effect depends on the cysteine-rich region of G (GCRR), a segment conserved in wild-type isolates worldwide. These findings reveal a novel function for the GCRR with potential implications for the generation of protective cellular responses and vaccine development.

Animals↗
PubMed2005

Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis.

Because chronic pulmonary diseases predispose to lung neoplasia, the identification of the molecular mechanisms involved could provide novel preventive, diagnostic, and therapeutic strategies. Toll-like receptors (TLRs) transduce exogenous and endogenous signals into the production of inflammatory cytokines to coordinate adaptive immune responses. To determine the role of Tlr4 in chronic lung inflammation, we compared lung permeability, leukocyte infiltration, and nuclear factor kappa B (NFkappaB) and activator protein 1 (AP-1) DNA binding in butylated hydroxytoluene (BHT)-treated (four weekly injections of 125-200 mg/kg each) inbred mouse strains with functional Tlr4 (OuJ and BALB) and mutated Tlr4 (HeJ and BALB(Lps-d)). We also measured primary tumor formation in these mice after single-carcinogen injection (3-methylcholanthrene; 10 microg/kg), followed by BHT treatment (six weekly injections of 125-200 mg/kg each). Mice with functional Tlr4 had reduced lung permeability, leukocyte inflammation, and primary tumor formation (BALB(Lps-d), mean = 22.3 tumors/mouse, versus BALB, mean = 13.9 tumors/mouse, difference = 8.4 tumors/mouse, 95% confidence interval = 4.6 to 12.1 tumors/mouse; P = .025) compared with mice with mutated Tlr4. NFkappaB DNA binding activity was higher in OuJ than in HeJ mice; however, AP-1 activity was elevated in HeJ mice. To our knowledge, this is the first model to demonstrate a modulatory role for Tlr4 in chronic lung inflammation and tumorigenesis.

Animals↗
PubMed2005

Gene-particulate matter-health interactions.

Inter-individual variation in human responses to air pollutants suggests that some subpopulations are at increased risk to the detrimental effects of pollutant exposure. Extrinsic factors such as previous exposure and nutritional status may influence individual susceptibility. Intrinsic (host) factors that determine susceptibility include age, gender, and pre-existing disease (e.g., asthma), and it is becoming clear that genetic background also contributes to individual susceptibility. Environmental exposures to particulates and genetic factors associated with disease risk likely interact in a complex fashion that varies from one population and one individual to another. The relationships between genetic background and disease risk and severity are often evaluated through traditional family-based linkage studies and positional cloning techniques. However, case-control studies based on association of disease or disease subphenotypes with candidate genes have advantages over family pedigree studies for complex disease phenotypes. This is based in part on continued development of quantitative analysis and the discovery and availability of simple sequence repeats and single nucleotide polymorphisms. Linkage analyses with genetically standardized animal models also provide a useful tool to identify genetic determinants of responses to environmental pollutants. These approaches have identified significant susceptibility quantitative trait loci on mouse chromosomes 1, 6, 11, and 17. Physical mapping and comparative mapping between human and mouse genomes will yield candidate susceptibility genes that may be tested by association studies in human subjects. Human studies and mouse modeling will provide important insight to understanding genetic factors that contribute to differential susceptibility to air pollutants.

Air Pollutants↗
PubMed2005

The cysteine-rich region of respiratory syncytial virus attachment protein inhibits innate immunity elicited by the virus and endotoxin.

The attachment protein (glycoprotein) of respiratory syncytial virus (RSV) has long been associated with disease potentiation and respiratory symptoms. The glycoprotein has a conserved cysteine-rich region (GCRR) whose function is unknown and which is not necessary for efficient viral replication. In this report, we show that the GCRR is a powerful inhibitor of the innate immune response against RSV, and that early secretion of glycoprotein is critical to modulate inflammation after RSV infection. Importantly, the GCRR is also a potent inhibitor of cytokine production mediated by several TLR agonists, indicating that this peptide sequence displays broad antiinflammatory properties. These findings have important implications for RSV pathogenesis and describe an inhibitor of TLR-mediated inflammatory responses that could have clinical applications.

Amino Acid Sequence↗
PubMed2005

Influence of genetic background on daily running-wheel activity differs with aging.

In humans, physical activity declines with age. We tested the hypothesis that genetic background and age interact to determine daily wheel-running physical activity patterns in mice. Five female mice from ten inbred strains (A/J, AKR/J, Balb/cJ, CBA/J, C3H/HeJ, C3Heb/FeJ, C57Bl/6J, C57L/J, DBA/2J, and SWR/J) were studied for 26 wk starting at 10 wk of age. All mice were housed in separate cages, each with a running wheel and magnetic sensor. Throughout the 26-wk period, age-related change in daily duration (P < 0.0001), daily distance (P < 0.0001), and average velocity (P = 0.0003) differed between the inbred strains. Unlike the other strains, SWR/J mice increased their running-wheel activity throughout the 6-mo time period. Broad-sense heritability estimations for the strains across the 26-wk period ranged between 0.410 and 0.855 for the three physical activity phenotypes. Furthermore, the broad-sense heritability estimates for daily running-wheel distance differed across time and suggested an interaction between genetic background and age on physical activity in these inbred mice.

Aging↗
PubMed2005

Role of Toll-like receptor-4 in genetic susceptibility to lung injury induced by residual oil fly ash.

The mechanisms of susceptibility to particle-induced lung injury are not clearly understood. To evaluate the contribution of genetic background to pulmonary pathogenesis, we compared the lung injury responses to residual oil fly ash (ROFA) in inbred mouse strains and calculated heritability estimates. Significant interstrain (genetic) variation was observed in ROFA-induced lung inflammation and hyperpermeability phenotypes; broad-sense heritability ranged from approximately 0.43 to 0.62, and the coefficient of genetic determination ranged from 0.28 to 0.45. C3H/HeJ (HeJ) mice were most resistant to the ROFA-induced injury responses. This was particularly important, as HeJ mice contain a dominant negative mutation in Toll-like receptor-4 (Tlr4). We then characterized ROFA-induced injury and TLR4 signaling in HeJ mice and its coisogenic strain C3H/HeOuJ (OuJ; Tlr4 normal) to understand the potential role of Tlr4 in this model. ROFA-induced lung injury was significantly greater in OuJ mice compared with HeJ mice. ROFA also significantly enhanced transcript and protein levels of lung TLR4 in OuJ but not in HeJ mice. Greater activation of downstream signal molecules (i.e., MYD88, TRAF6, IRAK-1, NF-kappaB, MAPK, AP-1) was observed in OuJ mice than in HeJ mice before the development of ROFA-induced pulmonary injury. Putative TLR4-dependent inflammatory genes that were differentially induced by ROFA in the two strains include interleukin-1beta and tumor necrosis factor-alpha. Results support an important contribution of genetic background to particle-mediated lung injury, and Tlr4 is a candidate susceptibility gene.

Animals↗
PubMed2005

Gene expression profiling of NRF2-mediated protection against oxidative injury.

Nuclear factor E2 p45-related factor 2 (NRF2) contributes to cellular protection against oxidative insults and chemical carcinogens via transcriptional activation of antioxidant/detoxifying enzymes. To understand the molecular basis of NRF2-mediated protection against oxidative lung injury, pulmonary gene expression profiles were characterized in Nrf2-disrupted (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice exposed to hyperoxia or air. Genes expressed constitutively higher in Nrf2(+/+) mice than in Nrf2(-/-) mice included antioxidant defense enzyme and immune cell receptor genes. Higher basal expression of heat shock protein and structural genes was detected in Nrf2(-/-) mice relative to Nrf2(+/+) mice. Hyperoxia enhanced expression of 175 genes (> or = twofold) and decreased expression of 100 genes (> or =50%) in wild-type mice. Hyperoxia-induced upregulation of many well-known/new antioxidant/defense genes (e.g., Txnrd1, Ex, Cp-2) and other novel genes (e.g., Pkc-alpha, Tcf-3, Ppar-gamma) was markedly greater in Nrf2(+/+) mice than in Nrf2(-/-) mice. In contrast, induced expression of genes encoding extracellular matrix and cytoskeletal proteins was higher in Nrf2(-/-) mice than in Nrf2(+/+) mice. These NRF2-dependent gene products might have key roles in protection against hyperoxic lung injury. Results from our global gene expression profiles provide putative downstream molecular mechanisms of oxygen tissue toxicity.

Animals↗
PubMed2005

Genetic aspects of pulmonary responses to inhaled pollutants.

Air pollution continues to be a major public health concern in industrialized cities throughout the world. Recent population and epidemiological studies that have associated ozone and particulate exposures with morbidity and mortality outcomes underscore the important detrimental effects of these pollutants on the lung. Inter-individual variation in human responses to air pollutants suggests that some subpopulations are at increased risk to the detrimental effects of pollutant exposure, and it has become clear that genetic background is an important susceptibility factor. Environmental exposures to inhaled pollutants and genetic factors associated with disease risk likely interact in a complex fashion that varies from one population to another. The relationships between the genetic background and disease risk and severity is often evaluated through traditional family-based linkage studies and positional cloning techniques. Case-control studies based on association of disease or disease subphenotypes with candidate genes may have certain advantages over family pedigree studies, and have become useful for understanding complex disease phenotypes. This is based in part on continued development of quantitative analysis and development of mapping technologies. Linkage analyses with genetically standardized animal models are useful to identify genetic determinants of host responses to environmental stimuli. For example, linkage analyses using inbred mice have identified chromosomal segments (quantitative trait loci, QTL) that contain genes that control susceptibility to the lung inflammatory and immune dysfunction responses to ozone, nitrogen dioxide, zinc oxide, and sulfate-associated particles. Candidate genes within the pollutant susceptibility QTLs have been tested for proof-of-concept using gene-targeting and overexpression models. Importantly, significant homology exists between the human and mouse genomes. Therefore, comparative mapping between the human and mouse genomes should yield candidate susceptibility genes that may be tested by association studies in humans. The combined human studies and mouse modeling will provide important insight to understanding genetic factors that contribute to differential susceptibility to pollutants in human populations.

Air Pollutants↗
PubMed2005

Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis.

The signal transducer and activator of transcription (Stat)-1 mediates growth arrest and apoptosis. We postulated that lung fibrosis characterized by excessive proliferation of lung fibroblasts would be enhanced in Stat1-deficient (Stat1-/-) mice. Two weeks after bleomycin aspiration (3 U/kg), Stat1-/- mice exhibited a more severe fibroproliferative response and significantly elevated total lung collagen compared to wild-type mice. Growth factors [epidermal growth factor (EGF) or platelet-derived growth factor (PDGF)] enhanced [3H]thymidine uptake in lung fibroblasts isolated from Stat1-/- mice compared to wild-type mice. Interferon (IFN)-gamma, which signals growth arrest via Stat1, inhibited EGF- or PDGF-stimulated mitogenesis in wild-type fibroblasts but enhanced [3H]thymidine uptake in Stat1-/- fibroblasts. Moreover, IFN-gamma treatment in the absence of growth factors induced a concentration-dependent increase in [3H]thymidine uptake in Stat1-/- but not wild-type fibroblasts. Mitogen-activated protein kinase (ERK-1/2) phosphorylation in response to PDGF or EGF did not differ among Stat1-/- and wild-type fibroblasts. However, Stat3 phosphorylation induced by PDGF, EGF, or IFN-gamma increased twofold in Stat1-/- fibroblasts compared to wild-type fibroblasts. Our findings indicate that Stat1-/- mice are more susceptible to bleomycin-induced lung fibrosis than wild-type mice due to 1) enhanced fibroblast proliferation in response to growth factors (EGF and PDGF), 2) stimulation of fibroblast growth by a Stat1-independent IFN-gamma signaling pathway, and 3) increased activation of Stat3.

Animals↗
PubMed2005

Association of CAT polymorphisms with catalase activity and exposure to environmental oxidative stimuli.

We tested the hypotheses that catalase activity is modified by CAT single nucleotide polymorphisms (SNPs) (-262;-844), and by their interactions with oxidant exposures (coal dusts, smoking), lymphotoxin alpha (LTA, NcoI) and tumor necrosis factor (TNF, -308) in 196 miners. Erythrocyte catalase, superoxide dismutase, and glutathione peroxidase activities were measured. The CAT -262 SNP was related to lower catalase activity (104, 87 and 72 k/g hemoglobin for CC, CT and TT, respectively, p < 0.0001). Regardless of CAT SNPs, the LTA NcoI but not the TNF-308 SNP was associated with catalase activity (p = 0.04 and p = 0.8). CAT -262 T carriers were less frequent in highly exposed miners (OR = 0.39 [0.20-0.78], p = 0.007). In CAT -262 T carriers only, catalase activity decreased with high dust exposure (p = 0.01). Haplotype analyses (combined CAT SNPs) confirm these results. Results show that CAT -262 and LTA NcoI SNPs, and interaction with coal dust exposure, influenced catalase activity.

Adult↗
PubMed2005

Genetic predisposition to latex allergy: role of interleukin 13 and interleukin 18.

BACKGROUND: Occupational exposure of healthcare workers to natural rubber latex has led to sensitization and potentially life-threatening anaphylaxis. Although environmental exposure to natural rubber latex products is necessary for sensitization, it is not sufficient. A number of genetic factors also seem to contribute to the latex sensitization; however, the multigenic nature of the allergic phenotype has made the identification of susceptibility genes difficult. The current study tests the hypothesis that known functional polymorphisms in genes encoding interleukin 4, interleukin 13, and interleukin 18 occur in a higher frequency in healthcare workers with natural rubber latex allergy. METHODS: Four hundred thirty-two healthcare workers with occupational exposure to natural rubber latex were screened using a clinical history questionnaire and latex-specific immunoglobulin E serology. Genomic DNA was extracted from peripheral blood lymphocytes and analyzed for single-nucleotide polymorphisms in candidate genes of interest. Data from cases and controls were analyzed by nominal logistic regression, with P < 0.05 considered significant. RESULTS: The latex allergy phenotype was significantly associated with promoter polymorphisms in IL13 -1055 (P = 0.02), IL18 -607 (P = 0.02), and IL18 -656 (P = 0.02) compared with nonatopic controls. CONCLUSIONS: The significant association of IL13 and IL18 promoter polymorphisms with latex allergy suggests a potential location for genetic control in the induction of latex allergy in individuals and extends the understanding of the genetic basis for the induction of immediate-type hypersensitivity in healthcare workers occupationally exposed to natural rubber latex.

Adult↗
PubMed2005

Gene-environment interactions in asthma and other respiratory diseases.

It is generally agreed that many lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) have polygenic inheritance, and that the association of a specific genotype or genotypes with the disease is likely to vary between populations. Furthermore, it is recognized that the etiology of many lung diseases involves a complex interplay between genetic background and exposure to multiple environmental stimuli, and understanding the mechanisms through which genes and environment interact represents a major challenge for pulmonary researchers. We discuss experimental approaches and challenges that must be overcome to identify disease genes for asthma, COPD and chronic bronchitis, and occupational lung diseases. In particular, common polymorphisms in CD14, glutathione S-transferase, and tumor necrosis factor alpha have been found to be important in gene-environment interaction and asthma pathogenesis. An understanding of gene-environment interactions in complex lung diseases is essential to the development of new strategies for lung disease prevention and treatment.

Asthma↗
PubMed2004

Genetic influence on daily wheel running activity level.

This project was designed to determine the genetic (between-strain) and environmental (within-strain) variance in daily running wheel activity level in inbred mice. Five male and five female mice, 9.7-15.3 wk old, from each of 13 strains (A/J, AKR/J, BALB/cJ, C3H/HeJ, C57Bl/6J, C57L/J, C3Heb/FeJ, CBA/J, DBA/2J, SWR/J, MRL/MpJ, SPRET/Ei, and CAST/Ei) as well as five female NZB/BinJ mice were housed individually. A running wheel in each cage was interfaced with a magnetic sensor to measure total daily distance and exercise time for each animal every 24 h for 21 consecutive days (3 wk). Average daily distance (km), duration (min), and velocity (m/min) for each strain was then calculated. Significant interstrain differences in average daily distance (P < 0.001), average daily exercise duration (P < 0.0001), and average daily exercise velocity (P < 0.0001) were found, with C57L/J mice running farther and faster than the other strains. Sex was a significant factor in daily running wheel activity, with female mice running an average of 20% farther (P = 0.01) and 38% faster (P < 0.0001) than male mice. The male mice ran 15% longer duration on a daily basis (P = 0.0091). Weight was only associated with exercise velocity in the female mice, but this relationship was not significant when subdivided by strain. Broad-sense heritability estimates on the physical activity differed by sex (for distance, male 31-48% and female 12-22%; for duration, male 44-61% and female 12-21%; for velocity, male 49-66% and female 44-61%). In conclusion, these data indicate that daily running wheel activity level in mice is significantly affected by genetic background and sex.

Animals↗