Super-Obesity is Associated With an Increased Risk of Complications Following Primary Total Knee Arthroplasty.

BACKGROUND: Obesity, defined as a body mass index (BMI) ≥ 30, is an ever-growing epidemic, with > 35% of adults in the United States currently classified as obese. Super-obese individuals, defined as those who have a BMI ≥ 50, are the fastest-growing portion of this group. This study sought to quantify the infection risk as well as the incidence of surgical, medical, and thromboembolic complications among super-obese patients undergoing total knee arthroplasty (TKA). METHODS: An all-payer claims database was used to identify patients who underwent elective, primary TKA between 2016 and 2021. Patients who had a BMI ≥ 50 were compared to those who had a normal BMI of 18 to 25. Demographics and the incidence of 90-days postoperative complications were compared between the 2 groups. Univariate analysis and multivariable regression were used to assess differences between groups. RESULTS: In total, 3,376 super-obese TKA patients were identified and compared to 17,659 patients who had a normal BMI. Multivariable analysis indicated that the super-obese cohort was at an increased postoperative risk of periprosthetic joint infection (adjusted odds ratio [aOR] 3.7, 95% confidence interval [CI]: 2.1 to 6.4, P < .001), pulmonary embolism (aOR 2.2, 95%-CI: 1.0 to 5.0, P = .047), acute respiratory failure (aOR 4.1, 95%-CI: 2.7 to 6.1, P < .001), myocardial infarction (aOR 2.5, 95%-CI: 1.1 to 5.8, P = .026), wound dehiscence (aOR 2.3, 95%-CI: 1.4 to 3.8, P = .001), and acute renal failure (aOR 3.2, 95%-CI: 2.4 to 4.2, P < .001) relative to patients who have normal BMI. CONCLUSIONS: Super-obese TKA patients are at an elevated risk of postoperative infectious, surgical, medical, and thromboembolic complications. As such, risk stratification, as well as appropriate medical management and optimization, is of utmost importance for this high-risk group.

Effects of 'Ice' flavoured e-cigarettes with synthetic cooling agent WS-23 or menthol on user-reported appeal and sensory attributes.

BACKGROUND: This clinical experiment tested the effects of exposure to e-cigarettes with WS-23 or menthol cooling additives on user appeal and sensory attributes, and, secondarily, whether WS-23 effects generalised across base characterising flavour, nicotine concentration, or nicotine/tobacco product use status. METHODS: In this within-participant double-blind experiment, adult tobacco/nicotine users administered standardised puffs of 18 different e-cigarette solutions in randomised sequences using a pod-style device. Each of three base characterising e-cigarette flavour solutions ('bold tobacco', 'mango,' 'wintergreen') in both 2% and 4% concentrations of nicotine benzoate salt were manipulated by adding either: (1) Menthol (0.5%), (2) WS-23 (0.75%) or (3) No cooling agent. After each administration, participants rated 3 appeal and 5 sensory attributes (0-100 scales). RESULTS: Participants (n=84; M(SD)=38.6 (13.6) years old) were either exclusive e-cigarette (25.0%), cigarette (36.9%) or dual (38.1%) users. WS-23 versus no coolant products produced higher liking, willingness to use again, smoothness, and coolness and lower disliking, bitterness, and harshness ratings (|B|difference range: 4.8 to 20.1; ps<0.005). Menthol (vs no coolant) increased willingness to use again and reduced harshness and coolness (ps<0.05). Flavours with WS-23 (vs menthol) were rated as smoother, cooler and less harsh (ps<0.05). Coolant effects did not differ by base flavour, nicotine concentration, or tobacco use status. CONCLUSIONS: Adding synthetic coolant WS-23 to e-cigarettes appears to make the vaping user experience more appealing, regardless of characterising base flavour. Regulatory agencies should be aware that the manufacturing process of adding synthetic coolants may increase the attractiveness of various e-cigarette products.Cite Now.

Glucagon-Like Peptide Receptor-1 Agonists Used for Medically-Supervised Weight Loss in Patients With Hip and Knee Osteoarthritis: Critical Considerations for the Arthroplasty Surgeon.

Patients with morbid obesity and concomitant hip or knee osteoarthritis represent a challenging patient demographic to treat as these patients often present earlier in life, have more severe symptoms, and have worse surgical outcomes following total hip and total knee arthroplasty. Previously, bariatric and metabolic surgeries represented one of the few weight loss interventions that morbidly obese patients could undergo prior to total joint arthroplasty. However, data regarding the reduction in complications with preoperative bariatric surgery remain mixed. Glucagon-like peptide receptor-1 (GLP-1) agonists have emerged as an effective treatment option for obesity in patients with and without diabetes mellitus. Furthermore, recent data suggest these medications may serve as potential anti-inflammatory and disease-modifying agents for numerous chronic conditions, including osteoarthritis. This review will discuss the GLP-1 agonists and GLP-1/glucose-dependent insulinotropic polypeptide dual agonists currently available, along with GLP-1/glucose-dependent insulinotropic polypeptide/glucagon triple agonists presently being developed to address the obesity epidemic. Furthermore, this review will address the potential problem of GLP-1-related delayed gastric emptying and its impact on the timing of elective total joint arthroplasty. The review aims to provide arthroplasty surgeons with a primer for implementing this class of medication in their current and future practice, including perioperative instructions and perioperative safety considerations when treating patients taking these medications.

Preoperative Laboratory Values Predicting Periprosthetic Joint Infection in Morbidly Obese Patients Undergoing Total Hip or Knee Arthroplasty.

BACKGROUND: Morbidly obese patients are an ever-growing high-risk population undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) for end-stage osteoarthritis. This study sought to identify preoperative laboratory values that may serve as predictors of periprosthetic joint infection (PJI) in morbidly obese patients undergoing THA or TKA. METHODS: All morbidly obese patients with preoperative laboratory data before undergoing primary elective TKA or THA were identified using the Premier Healthcare Database. Patients who developed PJI within 90 days after surgery were compared with patients without PJI. Laboratory value thresholds were defined by clinical guidelines or primary literature. Univariate and multivariable regression analyses were utilized to assess the association between PJI and preoperative laboratory values, including total lymphocyte count, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), albumin level, platelet count, albumin-globulin ratio, hemoglobin level, and hemoglobin A1c. RESULTS: Of the 6,780 patients identified (TKA: 76.67%; THA: 23.33%), 47 (0.69%) developed PJI within 90 days after surgery. The rate of PJI was 1.69% for patients with a hemoglobin level of <12 g/dL (for females) or <13 g/dL (for males), 2.14% for those with a platelet count of <142,000/µL or >417,000/µL, 1.11% for those with an NLR of >3.31, 1.69% for those with a PLR of >182.3, and 1.05% for those with an SII of >776.2. After accounting for potential confounding factors, we observed an association between PJI and an abnormal preoperative NLR (adjusted odds ratio [aOR]: 2.38, 95% confidence interval [CI]: 1.04 to 5.44, p = 0.039), PLR (aOR: 4.86, 95% CI: 2.15 to 10.95, p < 0.001), SII (aOR: 2.44, 95% CI: 1.09 to 5.44, p = 0.029), platelet count (aOR: 3.50, 95% CI: 1.11 to 10.99, p = 0.032), and hemoglobin level (aOR: 2.62, 95% CI: 1.06 to 6.50, p = 0.038). CONCLUSIONS: This study identified preoperative anemia, abnormal platelet count, and elevated NLR, PLR, and SII to be associated with an increased risk of PJI among patients with a body mass index of ≥40 kg/m 2 . These findings may help surgeons risk-stratify this high-risk patient population. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk.

In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we performed secondary and exploratory analysis of blood samples from a randomized clinical trial (NCT02158897) and show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging) and increased lymphoid to myeloid ratio: an indicator of immune system age. Based on a validated measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from  a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age.

The potential role of GLP-1 receptor agonist targeting in fertility-sparing treatment in obese patients with endometrial malignant pathology: a call for research.

INTRODUCTION: Most patients diagnosed with endometrial hyperplasia or cancer are obese. Obesity, along with polycystic ovarian syndrome (PCOS) and type-2 diabetes mellitus (T2DM), may act synergistically to increase risk of malignant endometrial pathology. Incidence of malignant endometrial pathology is increasing, particularly in reproductive aged women. In patients who desire future fertility, the levonorgestrel intrauterine device (LNG-IUD) is often utilized. If the first-line progestin therapy fails, there is not an effective second-line adjunct option. Moreover, pregnancy rates following fertility-sparing treatment are lower-than-expected in these patients. AREAS COVERED: This clinical opinion provides a summary of recent studies exploring risk factors for the development of malignant endometrial pathology including obesity, PCOS, and T2DM. Studies assessing efficacy of fertility-sparing treatment of malignant endometrial pathology are reviewed, and a potential new adjunct treatment approach to LNG-IUD is explored. EXPERT OPINION: There is an unmet-need for a personalized treatment approach in cases of first-line progestin treatment failure. Glucagon-like peptide 1 receptor agonists are a class of anti-diabetic agents, but may have a role in fertility-sparing treatment of obese patients with malignant endometrial pathology by reducing weight, decreasing inflammation, and decreasing insulin resistance; these changes may also improve chances of subsequent pregnancy. This hypothesis warrants further exploration.

Nutrition Care for Poorly Nourished Outpatients Reduces Resource Use and Lowers Costs.

BACKGROUND AND OBJECTIVES: Over 25% of United States (US) community-dwelling, older adults are at nutritional risk. Health and cost burdens of poor nutrition can be lowered by nutrition programs for hospital inpatients, but few studies have looked at the impact on outpatients. The objective of our study was to assess outcomes of a nutrition focused quality improvement program (QIP) on healthcare resource use and costs in poorly nourished outpatients. METHODS: This pre-post QIP study was implemented at 3 US healthcare system clinics. Included patients (n = 600) were ≥45 years old, had ≥2 chronic conditions, and were enrolled over a 15-month interval. For comparison, historical (n = 600) and concurrent control (n = 600) groups were used. Assessment of poor nutritional status was performed during each patient's baseline visit. Healthcare resource use (hospitalizations, emergency department visits, and outpatient clinic visits), medication use, and costs were determined for a 90-day interval. RESULTS: QIP patients (mean age 61.6 years) were predominantly female (62.5%) and overweight/obese (81.7%). The proportion of QIP outpatients presenting for healthcare services was significantly reduced compared to both historical and concurrent controls-relative risk reduction (RRR) versus historical (11.6%, P < .001) and versus concurrent (8.9%, P = .003). Of those who presented, RRR for healthcare resource use by QIP was significant in comparison with historical (12.9%, P = .022) but not concurrent controls. No significant differences were observed for medication usage. Lower resource use among QIP patients yielded total cost savings of $290 923 or per-patient savings of $485. CONCLUSIONS: Nutrition QIPs in outpatient clinics are feasible and can reduce healthcare resource use and cut costs. Such findings underscore benefits of nutritional interventions for community-dwelling outpatients with poor nutritional status.

Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome.

Angiogenesis and vascular remodeling support fibroproliferative processes; however, no study has addressed the importance of angiogenesis during fibro-obliteration of the allograft airway during bronchiolitis obliterans syndrome (BOS) that occurs after lung transplantation. The ELR(+) CXC chemokines both mediate neutrophil recruitment and promote angiogenesis. Their shared endothelial cell receptor is the G-coupled protein receptor CXC chemokine receptor 2 (CXCR2). We found that elevated levels of multiple ELR(+) CXC chemokines correlated with the presence of BOS. Proof-of-concept studies using a murine model of BOS not only demonstrated an early neutrophil infiltration but also marked vascular remodeling in the tracheal allografts. In addition, tracheal allograft ELR(+) CXC chemokines were persistently expressed even in the absence of significant neutrophil infiltration and were temporally associated with vascular remodeling during fibro-obliteration of the tracheal allograft. Furthermore, in neutralizing studies, treatment with anti-CXCR2 Abs inhibited early neutrophil infiltration and later vascular remodeling, which resulted in the attenuation of murine BOS. A more profound attenuation of fibro-obliteration was seen when CXCR2(-/-) mice received cyclosporin A. This supports the notion that the CXCR2/CXCR2 ligand biological axis has a bimodal function during the course of BOS: early, it is important for neutrophil recruitment and later, during fibro-obliteration, it is important for vascular remodeling independent of neutrophil recruitment.

A controlled trial of protein enrichment of meal replacements for weight reduction with retention of lean body mass.

BACKGROUND: While high protein diets have been shown to improve satiety and retention of lean body mass (LBM), this study was designed to determine effects of a protein-enriched meal replacement (MR) on weight loss and LBM retention by comparison to an isocaloric carbohydrate-enriched MR within customized diet plans utilizing MR to achieve high protein or standard protein intakes. METHODS: Single blind, placebo-controlled, randomized outpatient weight loss trial in 100 obese men and women comparing two isocaloric meal plans utilizing a standard MR to which was added supplementary protein or carbohydrate powder. MR was used twice daily (one meal, one snack). One additional meal was included in the meal plan designed to achieve individualized protein intakes of either 1) 2.2 g protein/kg of LBM per day [high protein diet (HP)] or 2) 1.1 g protein/kg LBM/day standard protein diet (SP). LBM was determined using bioelectrical impedance analysis (BIA). Body weight, body composition, and lipid profiles were measured at baseline and 12 weeks. RESULTS: Eighty-five subjects completed the study. Both HP and SP MR were well tolerated, with no adverse effects. There were no differences in weight loss at 12 weeks (-4.19 +/- 0.5 kg for HP group and -3.72 +/- 0.7 kg for SP group, p > 0.1). Subjects in the HP group lost significantly more fat weight than the SP group (HP = -1.65 +/- 0.63 kg; SP = -0.64 +/- 0.79 kg, P = 0.05) as estimated by BIA. There were no significant differences in lipids nor fasting blood glucose between groups, but within the HP group a significant decrease in cholesterol and LDL cholesterol was noted at 12 weeks. This was not seen in the SP group. CONCLUSION: Higher protein MR within a higher protein diet resulted in similar overall weight loss as the standard protein MR plan over 12 weeks. However, there was significantly more fat loss in the HP group but no significant difference in lean body mass. In this trial, subject compliance with both the standard and protein-enriched MR strategy for weight loss may have obscured any effect of increased protein on weight loss demonstrated in prior weight loss studies using whole food diets.

Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.

Previous reports have identified a circulating pool of CD45(+) collagen I(+) CXCR4(+) (CD45(+)Col I(+)CXCR4(+)) cells, termed fibrocytes, that traffic to areas of fibrosis. No studies have demonstrated that these cells actually contribute to fibrosis, however. Pulmonary fibrosis was originally thought to be mediated solely by resident lung fibroblasts. Here we show that a population of human CD45(+)Col I(+)CXCR4(+) circulating fibrocytes migrates in response to CXCL12 and traffics to the lungs in a murine model of bleomycin-induced pulmonary fibrosis. Next, we demonstrated that murine CD45(+)Col I(+)CXCR4(+) fibrocytes also traffic to the lungs in response to a bleomycin challenge. Maximal intrapulmonary recruitment of CD45(+)Col I(+)CXCR4(+) fibrocytes directly correlated with increased collagen deposition in the lungs. Treatment of bleomycin-exposed animals with specific neutralizing anti-CXCL12 Ab's inhibited intrapulmonary recruitment of CD45(+)Col I(+)CXCR4(+) circulating fibrocytes and attenuated lung fibrosis. Thus, our results demonstrate, we believe for the first time, that circulating fibrocytes contribute to the pathogenesis of pulmonary fibrosis.

Nonalcoholic fatty liver disease: pathogenesis, identification, progression, and management.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases in the absence of significant alcohol consumption, and its incidence is paralleling the increasing numbers of overweight and obese individuals worldwide. This review discusses the pathogenesis of NAFLD, including the roles potentially played by specific adipokines, such as TNF-alpha, leptin, and adiponectin. Clinical features, diagnosis, and potential methods of management are also addressed to assist practitioners with the management of this growing population of patients.

Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease.

Calorie restriction or changes in dietary composition can enhance healthy aging, but the inability of most subjects to adhere to chronic and extreme diets, as well as potentially adverse effects, limits their application. We randomized 100 generally healthy participants from the United States into two study arms and tested the effects of a fasting-mimicking diet (FMD)-low in calories, sugars, and protein but high in unsaturated fats-on markers/risk factors associated with aging and age-related diseases. We compared subjects who followed 3 months of an unrestricted diet to subjects who consumed the FMD for 5 consecutive days per month for 3 months. Three FMD cycles reduced body weight, trunk, and total body fat; lowered blood pressure; and decreased insulin-like growth factor 1 (IGF-1). No serious adverse effects were reported. After 3 months, control diet subjects were crossed over to the FMD program, resulting in a total of 71 subjects completing three FMD cycles. A post hoc analysis of subjects from both FMD arms showed that body mass index, blood pressure, fasting glucose, IGF-1, triglycerides, total and low-density lipoprotein cholesterol, and C-reactive protein were more beneficially affected in participants at risk for disease than in subjects who were not at risk. Thus, cycles of a 5-day FMD are safe, feasible, and effective in reducing markers/risk factors for aging and age-related diseases. Larger studies in patients with diagnosed diseases or selected on the basis of risk factors are warranted to confirm the effect of the FMD on disease prevention and treatment.

Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice.

An increase in fat mass associated with obesity results from recruitment and differentiation of adipocyte progenitor cells. The precise origin of these cells is unknown, although accumulating evidence suggests that circulating stem cells can differentiate into cells of mesenchymal lineage. It is currently unclear whether a progenitor adipocyte population exists in circulation. One potential candidate is the fibrocyte, which may represent a common progenitor cell for several mesenchymal lineages. We demonstrate that these circulating progenitors become adipocytes when cultured under adipogenic conditions, with intracellular lipids accumulation and up-regulation of proteins specific for adipocyte differentiation, including leptin, PPARgamma, and FABP4. cDNA microarray analysis revealed gene clusters that were differentially regulated during adipogenesis of fibrocytes, which were similar to visceral and subcutaneous adipose tissue preadipocyte-to-adipocyte differentiation. Moreover, these progenitors engrafted and formed human adipose tissue following injection into SCID mice. Although fibrocytes express an array of chemokine receptors, we observed an up-regulation of CCR2 expression following fibrocytes differentiation into adipocytes, which was associated with increased chemotactic response to CCL2. This paradigm supports the notion that elevated CCL2 levels in visceral adipose tissue associated with Metabolic Syndrome is a chemotactic niche, whereby fibrocytes can home to and differentiate into adipocytes to perpetuate its tissue formation.

Body weight loss with phentermine alone versus phentermine and fenfluramine with very-low-calorie diet in an outpatient obesity management program: a retrospective study.

BACKGROUND: Obesity, which is epidemic in the United States, is associated with increased morbidity and mortality. The combination of diet, exercise, and a behavior-modification program often does not result in ideal body weight. OBJECTIVE: The aim of this study was to determine the efficacy of phentermine (Phen) alone compared with phentermine plus fenfluramine (Phen-Fen), when used in combination with a very-low-calorie diet (VLCD) for weight loss in an outpatient obesity center. METHODS: We analyzed data collected at the UCLA outpatient University Obesity Center between 1993 and 1999. Data for patients who attended the center for at least 12 weeks and at least 4 visits, who were taking Phen or Phen-Fen, and whose body mass index (BMI) was ≥30 kg/m(2) were included in this retrospective study. RESULTS: During the study period, 3200 visits were recorded. Of 1133 potential participants, 446 patients were included in the analysis (309 women, 137 men; mean [SD] age, 46.7 [11.4] years; mean [SEM] body weight, 109.6 [26.7] kg; mean [SEM] BMI, 38.0 [7.6] kg/m(2)). Of these, 128 women and 60 men (mean [SEM] body weight at baseline, 103.4 [24.0] kg and 124.9 [28.2] kg, respectively) received Phen alone; 181 women and 77 men (mean [SEM] body weight at baseline, 102.5 [21.4] kg and 124.9 [30.2] kg, respectively) received Phen-Fen. No statistically significant differences were found between the Phen and Phen-Fen groups in mean age, body weight, or BMI for women or men at baseline. No significant differences in the time of weight loss were found when a VLCD was used with Phen alone compared with the Phen-Fen combination for either sex even at 12 weeks. For women, the mean total body weight loss was 7.4% in the Phen group and 8.7% in the Phen-Fen group, but these differences were not significant. For men, the mean total body weight loss was 7.8% in the Phen group and 8.2% in the Phen-Fen group, but these differences were not significant. No significant differences in BMI, severe adverse events, or dropout rate were found between the 2 treatment groups for men or women. CONCLUSIONS: This outpatient study did not detect any significant difference between adjunctive uses of Phen compared with Phen-Fen pharmacotherapy when used with VLCD over 12 weeks. Phen can be used to achieve significant weight loss when combined with VLCD. The tolerability and positive physical response further suggest that Phen is a valuable medication for obesity management in the outpatient setting.

Body fat and body-mass index among a multiethnic sample of college-age men and women.

Obesity prevalence and average body composition vary by US race and gender. Asian Americans have the lowest prevalence of obesity. Relying on body-mass index (BMI) to estimate obesity prevalence may misclassify subgroups that appear normally weighted but have excess body fat. We evaluated percentage body fat (PBF) and BMI to determine whether BMI reflects PBF consistently across different races. 940 college students were recruited from a local public university over four consecutive years. We measured PBF by bioelectrical impedance analysis (BIA), weight by physicians' scales, and height with stadiometers. Our sample comprised Asians (49%), Caucasians (23%), Hispanics (7%), and Other (21%). Participants averaged 21.4 years old; BMI was 22.9 kg/m(2); PBF was 24.8%. BMI and PBF varied significantly by race and gender (P value = 0.002 and 0.005 for men; 0.0009 and 0.0008 for women). Asian-American women had the lowest BMI (21.5 kg/m(2)) but the second highest PBF (27.8%). Linear association between BMI and PBF was the weakest (r (2) = 0.09) among Asian-American women and BMI had the poorest sensitivity (37%) to detect PBF. The high PBF with low BMI pattern exhibited by Asian-American women suggests that they could escape detection for obesity-related disease if BMI is the sole measure that estimates body composition.

Insulin, hs-CRP, leptin, and adiponectin. An analysis of their relationship to the metabolic syndrome in an obese population with an elevated waist circumference.

BACKGROUND: Various adipose tissue factors have been implicated as biomarkers of the metabolic syndrome (MS). The objective of this study was to assess which specific adipose tissue factors would discriminate the presence of MS in a strictly obese population meeting waist circumference (WC) criteria for the MS. METHODS: This was a cross-sectional study of 148 subjects recruited from a university-based weight loss program prior to starting the program. Patients were eligible if they had a BMI more than 25 kg/m(2) and had WC more than 40 and 35 inches in males and females, respectively. Biomarkers measured included high sensitivity C-reactive protein (hs-CRP), leptin, adiponectin, and total insulin. RESULTS: Of the total population, 33.8% satisfied criteria for the MS. Insulin was the only biomarker to consistently differentiate between presence and absence of MS in this obese population (P = 0.0001 in males, P = 0.006 in females). All biomarkers measured with the exception of leptin had a statistically significant relationship with increasing criteria for the MS. CONCLUSIONS: In a population where an excess amount of adipose tissue exists, insulin is the only reliable biomarker to differentiate MS status. We surmise that differences in hs-CRP, leptin, and adiponectin are a reflection of their measurements in individuals with statistically different amounts of adipose tissue.

Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma.

Fibrocytes are a distinct population of fibroblast-like progenitor cells in peripheral blood that have recently been shown to possess plasticity to differentiate along mesenchymal lineages, including commitment to myofibroblast and adipocyte cells. Here, we demonstrated that transforming growth factor (TGF) beta1 drives fibrocyte-to-myofibroblast differentiation through activating Smad2/3 and SAPK/JNK MAPK pathways, which in turn stimulates alpha-smooth muscle actin expression. We determined that SAPK/JNK signaling acts in a positive feedback loop to modulate Smad2/3 nuclear availability and Smad2/3-dependent transcription. Conversely, fibrocyte-to-adipocyte differentiation is driven by the peroxisome proliferator-activated receptor (PPAR) gamma agonist troglitazone, which is associated with cytoplasmic lipid accumulation and induction of aP2. Treatment with troglitazone also disrupted TGF beta 1-activated SAPK/JNK signaling, leading to decreased Smad2/3 transactivation activity and alpha-smooth muscle actin expression. Interestingly, TGF beta 1 was demonstrated to have reciprocal inhibition on fibrocyte differentiation to adipocytes. By activating SAPK/JNK signaling, which is normally suppressed during adipogenesis, PPARgamma-dependent transactivation activity and induction of aP2 expression were disrupted. Taken together, within the context of the local microenvironmental niche, the delicate balance of PPARgamma and TGF beta 1 activation drives the selection of an adipocyte or myofibroblast differentiation pathway through SAPK/JNK signaling.

CXCR2/CXCR2 ligand biology during lung transplant ischemia-reperfusion injury.

Lung transplantation is a therapeutic option for a number of end-stage pulmonary disorders. Early lung allograft dysfunction (ischemia-reperfusion injury) continues to be the most common cause of early mortality after lung transplantation and a significant risk factor for the development of bronchiolitis obliterans syndrome. Ischemia-reperfusion injury is characterized histopathologically by lung edema and a neutrophil predominate leukocyte extravasation. The specific mechanism(s) that recruit leukocytes to the lung during post-lung transplantation ischemia-reperfusion injury have not been fully elucidated. Because the ELR+ CXC chemokines are potent neutrophil chemoattractants, we investigated their role during post-lung transplantation ischemic-reperfusion injury. We found elevated levels of multiple ELR+ CXC chemokines in human bronchoalveolar lavage fluid from patients with ischemia-reperfusion injury. Proof of concept studies using a rat orthotopic lung transplantation model of "cold" ischemic-reperfusion injury demonstrated an increase in lung graft neutrophil sequestration and injury. In addition, lung expression of CXCL1, CXCL2/3, and their shared receptor CXCR2 paralleled lung neutrophil infiltration and injury. Importantly, inhibition of CXCR2/CXCR2 ligand interactions in vivo led to a marked reduction in lung neutrophil sequestration and graft injury. Taken together these experiments support the notion that increased expression of ELR+ CXC chemokines and their interaction with CXCR2 plays an important role in the pathogenesis of post-lung transplantation cold ischemia-reperfusion injury.