Translational Research - Articles in Press

Shortened activated partial thromboplastin time, a hemostatic marker for hypercoagulable state during acute coronary event - Uncorrected Proof

2010-03-08

Various factors may contribute to a hypercoagulable state and acute vascular thrombosis. A prospective study was conducted involving 165 coronary heart disease (CHD) patients from the Cardiology Unit, Hospital Universiti Sains Malaysia. This purpose of this study was to investigate the relationship among factor VIII (FVIII), prothrombin time (PT), activated partial thromboplastin time (APTT), and activated protein C resistance (APC-R) state among CHD patients and to look for potential clinical applications from these laboratory findings. There were 110 cases diagnosed as acute coronary syndrome, whereas another 55 were stable coronary artery disease patients. PT, APTT, FVIII, and APC-R assays were performed on all subjects. There was a significant difference between the FVIII level and the APTT results (P value < 0.0001). A negative relationship was found between the FVIII level and the APTT from linear regression analysis (R2 = 10%, P value < 0.0001). For each 1% increase in the FVIII level, the APTT was reduced by 0.013 s (95% CI between –0.019 and –0.007). Interestingly, none of the SCAD patients had abnormally short APTT. Approximately 68.4% of cases with a positive APC-R assay were found to have a high FVIII level. In conclusion, the APTT test is a potential hemostatic marker for hypercoagulable state including in arterial thrombosis.

Ibuprofen-induced hypersensitivity syndrome - Uncorrected Proof

Radu M. Nanau, Manuela G. Neuman — 2010-02-26

Ibuprofen is a widely used antipyretic and analgesic nonsteroidal antiinflammatory drug (NSAID). With the aging of the population, there will be a significant increase in the prevalence of painful degenerative and inflammatory rheumatic conditions. This increase likely will lead to a parallel increase in the use of NSAIDs, including ibuprofen. The primary effect of the NSAIDs is to inhibit cyclooxygenase (prostaglandin synthase), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes. Although in the majority of cases it is safe, this NSAID, ibuprofen, can produce an unpredictable, idiosyncratic, type B reaction that may pose a major concern in clinical practice. Type B reactions are known to occur in susceptible individuals. The true hypersensitivity reaction is a systemic disease defined by the triad of fever, rash, and internal organ involvement that starts 1 day to 12 weeks after the initiation of therapy Hypersensitivity reaction has limited the therapeutic use of many drugs, including ibuprofen. Hypersensitivity syndrome associated with ibuprofen is a host-dependent drug reaction that is idiosyncratic in nature. This reaction likely is caused by a combination of metabolic and immunologic factors. Immune mediated components, such as T-cell and their products cytokines and chemokines, can exacerbate cellular responses and create complex pathways that lead to a variety of clinical manifestations. Our review presents an ibuprofen-induced clinical manifestation of hypersensitivity syndrome and the necessity of wisely monitoring the patients clinically and by laboratory investigations when prescribing this drug.

From a distance: ventilation-dependent extra-pulmonary injury - Uncorrected Proof

Wolfgang M. Kuebler — 2010-02-26

Mechanical ventilation constitutes a life-saving intervention without adequate alternatives in acute respiratory failure; yet by itself, it may give rise to serious complications. In the lung, mechanical ventilation can result in pressure- or volume-dependent stress failure of alveolar epithelial and capillary endothelial barriers (referred to as baro- and volutrauma, respectively), a cyclic opening and collapse of alveoli with consequent wounding of epithelial cells (atelectrauma), or the provocation of lung parenchymal and inflammatory responses by mechanical stress (biotrauma). The recognition that reduction of tidal volumes from 12-mL/kg to 6-mL/kg body weight (bw) significantly reduces mortality in mechanically ventilated patients with acute respiratory distress syndrome (ARDS) highlighted the clinical relevance of these concepts and initiated the introduction of lung-protective ventilation strategies into the clinic scenario.

Appreciation to Reviewers - Uncorrected Proof

Jeffrey Laurence, Michael Franklin — 2010-02-24

We wish to acknowledge the outstanding contribution of our reviewers and Editorial Advisory Board. The quality and breadth of the Journal is only made possible by the dedicated efforts of our reviewers.

Serum levels of apelin and ghrelin in patients with acute coronary syndromes and established coronary artery disease—KOZANI STUDY - Uncorrected Proof

2010-02-22

Apelin and ghrelin have emerged as novel adipokines, but their role in coronary artery disease (CAD) remains obscure. In the present study, we analyzed their serum levels in patients with acute coronary syndromes (ACS) or established asymptomatic CAD. A total of 355 participants were enrolled. Among them were 80 patients with unstable angina (UA) and 115 patients with acute myocardial infarction (AMI) hospitalized in the coronary care unit. We also included 88 asymptomatic patients with established CAD (asymptomatic CAD) and 72 age-and sex-matched healthy controls (HCs). All groups with CAD underwent coronary angiography, and the Gensini score was determined. Clinical parameters, glycemic and lipid profile, high-sensitivity CRP (hsCRP), insulin resistance (HOMA-IR), as well as apelin and ghrelin were assayed. Patients with ACS (UA or AMI) were sampled at hospital admission. All 3 groups with CAD (UA, AMI, or asymptomatic CAD) showed significantly higher levels of hsCRP, HOMA-IR, and white blood cells than controls (P < 0.01). Conversely, apelin and ghrelin concentrations were considerably (P < 0.05) lower in CAD patients with respect to the control group. Most importantly, UA (6.72 ± 3.51 ng/mL) and AMI (6.02 ± 4.07 ng/mL) groups had even lower apelin levels on admission compared with the asymptomatic CAD group (13.53 ± 5.2 ng/mL) (P < 0.05). Logistic regression analysis showed an independent association of low apelin and ghrelin levels with CAD presence. Besides this result, apelin showed an inverse relationship with ACS incidence and a Gensini score independent of other cardiovascular risk factors (P < 0.05). In conclusion, CAD seemed to correlate with low serum apelin and ghrelin levels. Moreover, apelin concentrations inversely were associated with the severity and the acute phase of CAD, which suggests its involvement in the progression and destabilization of coronary atherosclerotic plaques.

New type of human blood stem cell: a double-edged sword for the treatment of type 1 diabetes - Uncorrected Proof

2010-02-15

Type 1 diabetes (T1D) is an autoimmune disease caused by an autoimmune destruction of pancreatic islet insulin-producing cells. Autoimmunity and shortage of insulin-producing cells are 2 key issues for the treatment of T1D. To cure T1D in a comprehensive manner, both issues need to be addressed simultaneously. Not only must the islet cells be replaced, the patient's immune system also must be dealt with. Regulatory T cells (Tregs) play a crucial role in maintaining homeostasis and self-tolerance through their inhibitory impacts on autoreactive effector T cells. We identified a novel type of stem cells from human umbilical cord blood, designated cord blood stem cells (CB-SC), which may be able to address immune modulation of the autoimmune process and allow for β-cell replacement. We are the first group using CB-SC to correct functional defects of CD4+CD62L+ Tregs, leading to a reversal of overt diabetes in an autoimmune-caused diabetic NOD mouse model. Notably, treatment with CB-SC-modulated CD4+CD62L+ Tregs (mCD4CD62L Tregs) simultaneously can overcome the autoimmunity via systemic and local immune modulations and the shortage of insulin-producing cells via stimulating the β-cell regeneration. These new stem cells will offer a promising avenue for the development of powerful autologous therapeutic products for prevention and reversal of T1D.

Lung–lung interaction in isolated perfused unilateral hyperventilated rat lungs - Uncorrected Proof

2010-02-11

The technique of conducting high tidal volume (TV) ventilation-induced lung inflammation including remote organs is still open to discussion, and our aim is to investigate this issue in isolated ventilated rat lungs perfused with salt solution. Selective right lung (RL) hyperventilation (TV of 15 mL/kg with air containing 5% CO2 on zero or 2.5 cm H20 zero end expiratory pressure [ZEEP] as well as positive end-expiratory pressure [PEEP]), in addition to left lung (LL) on 2.5 cm H20 continuous positive airway pressure (CPAP) for 60 min, was realized after 30 min. The ventilation technique was applied to both lungs by occluding the left main bronchus, and it was allocated to the following 5 groups: groups 1 and 2 underwent hyperventilation under ZEEP, groups 3 and 4 underwent ventilation under PEEP with recirculation or nonrecirculation (R-ZEEP or NR-ZEEP and R-PEEP or NR-PEEP), and group 5 served as the control group. Recirculation means the same perfusate recirculates the system throughout the procedure. The wet/dry ratio and protein content of bronchoalveolar lavage fluid (Prot-BALF), cytokine messenger RNAs (mRNAs), localization of tumor necrosis factor-α (TNF-α), immunofluorescence double(staining TNF-α concentration in the perfusate, and BALF in each lung were measured and compared between groups by Kruskal-Wallis test. Lung injury (increased wet/dry ratio, Prot-BALF, and TNF-α on endothelial and epithelial cells) was shown in the hyperventilated RLs with ZEEP compared with their corresponding CPAP LLs. PEEP prevented these injuries. Lung injury was also demonstrated in the recirculated LL compared with the nonrecirculated LL (Prot-BALF, TNF-α, and interleukin-1β [IL-1β] mRNAs: the LL of the R-ZEEP is greater than the LL of nonrecirculation with PEEP [NR-ZEEP] by P < 0.01). Unilateral hyperventilated lungs with ZEEP induced TNF-α, increased permeability, and injured the control lung via perfusion.

Markers of bone remodeling and skeletal morbidity in patients with solid tumors metastatic to the skeleton receiving the biphosphonate zoledronic acid - Uncorrected Proof

2010-02-08

The molecular triad, which includes the receptor activator of nuclear factor kappa-B ligand (RANKL), its receptor RANK, and the endogenous soluble RANKL decoy receptor osteoprotegerin (OPG), has emerged as an important determinant of bone metabolism. We aimed to evaluate the effect of treatment with the biphosphonate zoledronic acid (ZA) on biochemical markers of bone remodeling and to detect possible correlations of marker-level changes with skeletal morbidity and clinical outcomes in patients with solid tumors and osseous metastases. The following serum markers were measured at the onset of skeletal metastases and after 6 months of treatment with ZA (4 mg intravenously monthly) in 70 patients with breast (n = 30), lung (n = 18), or prostate (n = 22) cancer: RANKL, OPG, C-terminal cross-linking telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), bone-specific alkaline phosphatase (bALP), and osteopontin (OPN). Logistic regression models were applied to assess the correlation between marker-level changes and skeletal related events (SRE, primary endpoint), recurrence or progression, and death. Within a median follow-up of 32 months, 34 patients (48.6%) presented with at least 1 SRE and 48 patients (68.6%) relapsed. The RANKL/OPG ratio was upregulated in patients with breast and lung cancer, and it tended to decline after treatment with ZA, whereas prostate cancer patients presented with profound elevation of OPG only that persisted after treatment. CTX levels were significantly reduced after treatment in the whole study population (P = 0.003). None of the markers was able to predict skeletal morbidity or clinical outcomes independently of well-established prognostic clinical parameters.

Telomeres and type 2 diabetes - Uncorrected Proof

Frederick G. Hamel — 2010-01-20

The importance of telomeres in molecular biology and disease was highlighted recently by the awarding of the 2009 Nobel Prize in Physiology or Medicine to Elizabeth H. Blackburn, Carol W. Greider, and Jack W. Szostak for “How chromosomes are protected by telomeres and the enzyme telomerase” (http://nobelprize.org/nobel_prizes/medicine/laureates/2009/press.html). Thus, the publication in this issue of the article by Zee et al relating telomere length shortening and type 2 diabetes mellitus is timely. Shortened telomeres have been associated with diabetes in previous studies, but they have generally used smaller patient numbers. This article by Zee et al, along with another report by Salpea et al not yet published, should establish firmly the link between telomere length and type 2 diabetes mellitus. Several recent review papers on telomeres are available, which serve as the basis for this commentary.

Combination drug–diet therapies for dyslipidemia - Uncorrected Proof

2010-01-20

Expense, high drug dose, and low compliance to strict dietary therapies are current issues surrounding modern drug- and diet-based lipid-lowering approaches. Furthermore, variable patient outcomes and suboptimal response to both drug and diet therapies are increasingly evident. Therefore, the question arises as to whether more emphasis should be placed on the combination diet/drug therapies to reduce cholesterol levels in patients who respond suboptimally to diet and drug monotherapies. Although considerable research has explored multidrug combination therapies, combination drug/diet therapies receive less attention. However, combined drug/diet approaches may reduce the number of drug prescriptions, the progressive increase in “optimal” drug dosage, and costs associated with pharmaceutical disease management. Future research priorities in drug/diet therapeutic approaches should not only emphasize the discovery of novel combinations but also should address potential safety issues prior to wide-scale acceptance in clinical practice. Accordingly, this review will assess current limitations associated with both drug and diet lipid-lowering therapies and explore the potential of combination drug/diet therapies in the treatment of dyslipidemia.

Type 1 von Willebrand disease due to reduced von Willebrand factor synthesis and/or survival: observations from a case series - Uncorrected Proof

2009-12-31

It may be difficult to diagnose type 1 von Willebrand disease (VWD) because of its heterogeneous and sometimes elusive nature. To evaluate the contribution of a shorter von Willebrand factor (VWF) survival in a modulating VWD phenotype, the VWF half-life was assessed in 45 type 1 VWD patients using a 24-h 1-desamino-8-d-arginine vasopressin (DDAVP) test. A shorter VWF survival was observed in patients with C1130F mutations (T1/2 elimination [T1/2el]=4.6±1.0h vs normal=15.8±2.3h, P<0.0001), in those with other missense mutations investigated (T1/2el=9.5±0.9h, P<0.02), and in patients not carrying VWF mutations (T1/2el=7.0±0.7h, P<0.001); the decrease mainly depended on a greater VWF clearance. VWF survival and clearance were normal in patients who carried nonsense mutations. The VWF-propeptide-to-VWF-antigen (VWF:Ag) ratio (VWFpp ratio) was higher in patients with a shorter VWF survival, and the values were inversely correlated with the VWF half-life (P<0.01). The response of VWF to DDAVP administration, which is useful to explore the synthesis and storage of VWF, was normal in patients with no mutations, whereas it decreased in patients with missense and nonsense mutations. Three scenarios, thus, are recognizable in type 1 VWD; one is associated mainly with a shorter survival of VWF, another is associated with its reduced synthesis and release, and a third is characterized by a combination of the 2. The shorter VWF half-life found in patients with no VWF mutations suggests that mechanisms other than VWF might be involved in the pathogenesis of type 1 VWD.

Cholesterol in pleural exudates depends mainly on increased capillary permeability - Uncorrected Proof

2009-12-25

Pleural fluid (PF) cholesterol is a useful parameter to differentiate between pleural transudates and exudates, although the pathophysiologic mechanisms for its increase in exudates are not fully understood. We aim to elucidate the cause of this increase by analyzing the levels of cholesterol—high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), apoprotein A (ApoA), and apoprotein B (ApoB)—in PF and blood as well as the number of leucocytes and red cells in the PF. We studied 259 patients with pleural effusion (57 transudates and 202 exudates). The correlations of the pleural and serum (S) levels of these parameters were analyzed, with the pleural cholesterol fractions as the dependent variables and their levels in blood and the pleural/serum protein ratio (P/S prot ratio) as the independent variables. The pleural fluid cholesterol levels (PFCHOL) correlated with their blood levels and the capillary permeability (r=0.885). No significant differences were found between the percentage of LDL, with regard to total cholesterol in the blood (concentration of cholesterol in the serum [SCHOL]), and the same percentage in the exudates, between the PF/S LDL ratio (0.46) and the PF/S CHOL ratio (0.48), or between the PF/S ApoB ratio and the PF/S LDL ratio. The percentage of PF cholesterol bound to HDL and LDL was significantly higher (91.9%) than in the blood (90%). No significant correlations were found between any of the lipids studied and the number of erythrocytes and leucocytes. In conclusion, the PFCHOL may be predicted from the SCHOL, and the capillary permeability may be reflected by the PF/S prot ratio.

The role of ATP-binding-cassette-transporter-A1 (ABCA1) gene polymorphism on coronary artery disease risk - Uncorrected Proof

Mahmoud Doosti, Mahdi Najafi, Javad Zavar Reza, Abdolrahim Nikzamir — 2009-12-25

ATP-binding cassette transporter A1 (ABCA1) plays a pivotal role in intracellular cholesterol removal and exerts a protective effect against atherosclerosis. The role of genetic factors in susceptibility to coronary artery disease (CAD) is not clear. The aim of this study was to evaluate for the first time the possible association between R219K gene polymorphism and coronary artery disease in an Iranian adult population. A total of 207 consecutive patients with CAD (group A) and 94 patients without CAD (group B) were studied. We determined the presence of the R219K variant in the ABCA1 gene by polymerase chain reaction (PCR) and restriction analysis in 301 patients with and without CAD. The distribution of genotypes among the 2 groups was significantly different (P=0.009). In univariate analysis (with genotype AA as reference), the GG genotype was associated with a significantly increased risk of CAD (P=0.002; odds ratio [OR]=2.761; 95% confidence interval [CI]=1.418–5.374), but the GA genotype did not show a significant association (P=0.234) (data not shown). A multivariate logistic regression analysis (using sex as clinically significant variable, and using age, diabetes mellitus, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein [HDL], smoking, body mass index [BMI], and genotype as statistically significant variables) was used to determine independent associations and adjusted ORs. The GG genotype (compared with the AA genotype) was an independent predictor of CAD (OR=2.856, 95% CI=1.307–6.241; P=0.009), followed by BMI (P=0.034; OR=1.100; 95% CI=1.007–1.200). The GG genotype in the ABCA1 gene is independently associated with CAD in Iranian patients.

Isoenzyme profile of glutathione transferases in transitional cell carcinoma of upper urinary tract - Uncorrected Proof

2009-12-18

Upregulated glutathione S-transferase P1 (GSTP1) plays an important role in the resistance to apoptosis in transitional cell carcinoma (TCC) of the urinary bladder (UB) and represents a potential target for chemotherapeutic agents. Our aim was to perform a systematic investigation of a glutathione S-transferase (GST) isoenzyme profile (GSTM, GSTP1, and GSTT1) in the upper urinary tract (UUT) TCC and compare it with the GST isoenzyme pattern of the UB TCC and normal urothelium. We examined GST activity spectrophotometrically by using substrates for the overall GST activity, GSTP1, and GSTT1 in the cytosolic fraction. GSTP1 and GSTM expression was analyzed by Western blotting. The results obtained have shown that the overall GST activity was significantly greater in UUT TCC in comparison with urothelium (P<0.001), which gradually increases with tumor grade (P<0.05). The mean GSTP1 and GSTT1 activities in UUT TCC were 2- and 3.6-fold higher, respectively, than in the normal urothelium (P<0.001), and these values did not differ significantly from activities found in the UB TCC. GSTM was expressed in 42% of the UUT TCC and 50% of the UB TCC specimens. The level of GSTM expression was slightly increased in the UUT TCC specimens in comparison with normal urothelium (P>0.05). We conclude that 3 major cytosolic GST classes, GSTM, GSTP1, and GSTT1, are expressed in the UUT TCC. The isoenzyme profile of GST in the UUT TCC is similar to that observed in the UB TCC; it shows essentially the same alteration of the GST phenotype in the course of cancerization. The association of GSTT1 and GSTP1 upregulation with the malignant phenotype of the UUT TCC might result in resistances to both chemotherapy and apoptosis.

Health-related quality of life in Hispanics with chronic kidney disease - Uncorrected Proof

Anna C. Porter, Julio C. Vijil, Mark Unruh, Claudia Lora, James P. Lash — 2009-11-16

Health-related quality of life (HRQOL) is an important patient-reported outcome that has gained attention in research and clinical practice. In recent years, reports of chronic kidney disease (CKD) have increased. However, not much information is available for Hispanics with CKD, a group whose rates of incidents are on the rise. This review discusses the measurement of HRQOL in CKD, with a particular focus on issues pertaining to Hispanics. Future research directions also are discussed.

Nuclear factor-kappa B (NFκB) component p50 in blood mononuclear cells regulates endothelial tissue factor expression in sickle transgenic mice: implications for the coagulopathy of sickle cell disease - Uncorrected Proof

2009-11-13

Sickle cell anemia is accompanied by the activation of coagulation and thrombosis. We have studied the abnormal expression of tissue factor (TF) by the pulmonary vein endothelium of the mild-phenotype NY1DD sickle transgenic. As detected by immunofluorescence microscopy, this occurs only after the NY1DD mouse is exposed to hypoxia/reoxygenation (H/R), which actually causes ischemia/reperfusion in the sickle cell disease—but not the normal—mouse model. We tested the hypothesis that the nuclear factor-kappa B (NFκB)-activating inflammation that develops in post-H/R NY1DD mice is responsible for this phenotype switch. Various NFκB inhibitors (including p50-specific andrographolide) demonstrated that endothelial TF positivity is NFκB dependent. Several systemic inflammatory stimulators (tumor necrosis factor [TNFα], lipopolysaccharide, thioglycollate, and carageenan) given to control mice showed that the inflammatory promotion of TF expression by only pulmonary vein endothelium is not specific to the sickle cell disease model. We bred the NFκB(p50)-/- state into the NY1DD mouse. Combined with marrow transplantation, this allowed the creation of NY1DD mice that were NFκB(p50)-/- only in peripheral blood cells (and marrow) versus only in vessel walls (and tissues). This process revealed that endothelial TF expression in the NY1DD mouse is highly dependent on NFκB(p50) in peripheral blood mononuclear cells—but not in the vessel wall. In confirmation, the infusion of post-H/R sickle mouse blood mononuclear cells into naïve NY1DD mice stimulated endothelial TF expression; the infusion of such cells from unstimulated sickle cell disease mice at ambient air did not stimulate TF expression. We conclude that peripheral blood mononuclear cells indirectly promote endothelial TF expression via a NFκB(p50)-dependent mechanism. This approach may be relevant to the role of coagulopathy in clinical sickle cell disease.

Mean leukocyte telomere length shortening and type 2 diabetes mellitus: a case-control study - Uncorrected Proof

2009-10-23

Recent data have implicated leukocyte telomere length shortening as a potential risk predictor for type 2 diabetes mellitus (T2DM) and its associated phenotypes. However, to date, epidemiologic data are scarce. Using a case-control study from a community-based population sample of the Boston metropolitan area (all whites: 424 controls and 432 cases), we examined the relationship of mean leukocyte telomere repeat copy number to single gene copy number (TSR) and T2DM. Associations of loge-transformed TSR with age, race, sex, body mass index (BMI), current smoking status, fasting insulin levels, fasting glucose levels, and hemoglobin A1c (HbA1c) were examined by multivariable linear regression analysis. A logistic regression analysis was performed to evaluate the association of loge-transformed TSR with T2DM with or without adjustment for potential confounders. The loge-transformed TSR was significantly shorter in the white cases than the white controls (P=0.003). In a multivariable linear regression analysis, an inverse association of loge-transformed TSR with BMI was observed (P=0.04). Furthermore, in a multivariable logistic regression analysis, decreased loge-transformed TSR was significantly associated with T2DM (adjusted odds ratio=1.748; 95% confidence interval [CI]=1.015–3.012; P=0.044). In summary, the current investigation has shown an association of mean leukocyte telomere length shortening with T2DM in white subjects. If corroborated in other studies, our findings suggest the potential importance of telomere biology in T2DM.

Foreign body-induced granulation tissue is a source of adult stem cells - Uncorrected Proof

2009-09-23

In the current study, we have cultured and propagated the cells obtained from the granulation tissue that forms around perforated polyvinyl tubes placed in the subcutaneous space of normal rats. We found that these cells (called granulation tissue-derived stem cells [GTSCs]) expressed markers of embryonic pluripotent cells (Oct-4 and Nanog) and of adult stem cells (CXCR4 and Thy1.1) as well as produced high levels of vascular endothelial growth factor (VEGF) for up to 10 passages. By fluorescence-activated cell-sorting (FACS) analysis, GTSCs were positive for stem-cell surface markers CD90, CD59, and CD44 and were negative for CD45, which suggests that they were of mesenchymal origin and not of hematopoietic lineage. When incubated in specific differentiation medium, these cells transformed into adipogenic, osteogenic, and chondrogenic lineages, which shows that they were multipotent. Furthermore, after systemic injection, these cells were found in the vicinity of an injured site created in the liver but not in normal areas of the liver, which indicates their propensity to seek and engraft to an injured area in the body. We conclude that granulation tissue induced by a large foreign body is a convenient source of adult stem cells that can be maintained in culture and can be used to repair and regenerate injured tissue.

γδ T cells and Th17 cytokines in hypersensitivity pneumonitis and lung fibrosis - Uncorrected Proof

2009-08-24

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease caused by repeated inhalation of aerosolized antigens. With chronic exposure to an inhaled antigen, patients are at risk of developing irreversible pulmonary fibrosis and increased morbidity and mortality. Although αβ T cells have been shown to be important in the pathogenesis of HP, γδ T cells are also found and may protect against lung damage and fibrosis caused by chronic exposure to an inhaled pathogen. Th1 cytokines have been implicated in the pathogenesis of HP; yet patients with HP still develop pulmonary fibrosis suggesting that other T-cell cytokines may be involved. Th17 cytokines are a novel group of effector molecules expressed by various T lymphocytes, including γδ T cells. Th17-expressing γδ T cells are important for mucosal immunity against invading microbial pathogens and other inhaled antigens. An increased understanding of γδ T cells that express Th17 cytokines in HP may lead to the development of novel therapeutic and clinical strategies that prevent fibrotic lung disease in patients with HP.