The Onset and Development of Patella Alta in Children With Patellar Instability.

BACKGROUND: Patella alta is an anatomic risk factor for patellar instability in adolescents that is also linked to the risk factor of trochlear dysplasia. This study aims to determine the age of onset and age-related incidence of patella alta in a pediatric population of patients with patellar instability. We hypothesized that patellar height ratios would not increase with age, suggesting a congenital rather than the developmental origin of patella alta. METHODS: A retrospective cross-sectional cohort of patients was collected with the following inclusion criteria: patients aged 5 to 18 who had a knee magnetic resonance imaging performed from 2000 to 2022 and the International Classification of Diseases code for patellar dislocation. Demographic information and details of the patellar instability episode(s) were collected with a chart review. Sagittal magnetic resonance imaging was used to measure Caton-Deschamps Index (CDI) and the Insall-Salvati Ratio (ISR) by 2 observers. Data were analyzed to assess for associations between patellar height ratios and age of the first dislocation and to assess if the proportion of patients categorized as having patella alta changed with age. RESULTS: The 140 knees included in the cohort had an average age of 13.9 years (SD=2.40; range: 8-18) and were 55% female. Patella alta was present in 78 knees (55.7%) using CDI>=1.2 and in 59 knees (42.1%) using ISR>=1.3. The earliest age patella alta was observed was at age 8 using CDI>=1.2 and age 10 using ISR>=1.3. There were no statistically significant associations between CDI and age without adjustment ( P =0.14) nor after adjustment for sex and body mass index ( P =0.17). The proportion of knees above the CDI threshold for patella alta to the knees below the cutoff did not show a significant change with age ( P =0.09). CONCLUSIONS: Patella alta, as defined by CDI, is seen in patients as young as 8 years old. Patellar height ratios do not change with age in patients with patellar dislocation, suggesting that patella alta is established at a young age rather than developing during the adolescent years. LEVEL OF EVIDENCE: Level III-diagnostic, cross-sectional.

Increased Joint Space Narrowing After Arthroscopic Partial Meniscectomy: Data From the Osteoarthritis Initiative.

BACKGROUND: Arthroscopic partial meniscectomy (APM) is widely performed and remains an important therapeutic option for patients with a meniscal tear. However, it is debated whether or not APM accelerates the progression of osteoarthritis (OA) in the long term. PURPOSE/HYPOTHESIS: The purpose was to compare the progression of OA measured by the change in tibiofemoral joint space width (JSW)-a quantitative measure of OA radiographic severity-across 3 groups with a midterm follow-up: (1) patients undergoing APM; (2) those with a meniscal tear treated nonoperatively; and (3) those without a tear. We hypothesized that the reduction in JSW would be greatest in patients undergoing APM and least in those patients without a tear. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Using the Osteoarthritis Initiative cohort, a total of 144 patients were identified that underwent APM with at least 12 months of follow up and without previous knee surgery. Those with a meniscal tear who did not have APM (n = 144) and those without a tear (n = 144) were matched to patients who had APM by sex, age, Kellgren-Lawrence (KL) grade, and follow up time. Participants underwent magnetic resonance imaging at baseline. Knee radiographs to assess JSW were collected annually or biannually. The change in minimum medial compartment JSW was calculated using a validated automated method. A piecewise linear mixed effects model was constructed to examine the relationship between JSW decline over time and treatment group-adjusting for age, body mass index, smoking status, KL grade, and baseline JSW. RESULTS: All groups had comparable baseline JSW-ranging from 4.33 mm to 4.38 mm. The APM group had a rate of JSW decline of -0.083 mm/mo in the first 12 months and -0.014 mm/mo between 12 and 72 months. The rate of JSW decline in the APM group was approximately 27 times greater in the first 12 months than that in the nonsurgical group (-0.003 mm/mo) and 5 times greater than that in the no tear group (-0.015 mm/mo); however, there was no significant difference between groups for 12 to 72 months (nonsurgical group: -0.009 mm/mo; no tear group: -0.010 mm/mo). The adjusted JSW in the APM group was 4.38 mm at baseline and decreased to 2.57 mm at 72 months; the JSW in the nonsurgical group declined from 4.31 mm to 3.73 mm, and in the no tear group it declined from 4.33 mm to 3.54 mm. There was a statistically significant difference in JSW change between baseline and 72 months for the APM group compared with the other groups (P < .001), but not between the nonsurgical and no tear groups (P = .12). CONCLUSION: In the first postoperative year, APM results in a faster rate of joint space narrowing compared with knees undergoing nonsurgical management of meniscal tears. Thereafter, there are comparable rates of OA progression regardless of the chosen management. APM results in a persistent decrease in JSW over at least 72 months. An untreated meniscal tear does not contribute to radiographic progression-assessed by JSW-as compared with an intact meniscus.

Meniscal Treatment as a Predictor of Worse Articular Cartilage Damage on MRI at 2 Years After ACL Reconstruction: The MOON Nested Cohort.

BACKGROUND: Patients undergoing anterior cruciate ligament reconstruction (ACLR) are at an increased risk for posttraumatic osteoarthritis (PTOA). While we have previously shown that meniscal treatment with ACLR predicts more radiographic PTOA at 2 to 3 years postoperatively, there are a limited number of similar studies that have assessed cartilage directly with magnetic resonance imaging (MRI). HYPOTHESIS: Meniscal repair or partial meniscectomy at the time of ACLR independently predicts more articular cartilage damage on 2- to 3-year postoperative MRI compared with a healthy meniscus or a stable untreated tear. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A consecutive series of patients undergoing ACLR from 1 site within the prospective, nested Multicenter Orthopaedic Outcomes Network (MOON) cohort underwent bilateral knee MRI at 2 to 3 years postoperatively. Patients were aged <36 years without previous knee injuries, were injured while playing sports, and had no history of concomitant ligament surgery or contralateral knee surgery. MRI scans were graded by a board-certified musculoskeletal radiologist using the modified MRI Osteoarthritis Knee Score (MOAKS). A proportional odds logistic regression model was built to predict a MOAKS-based cartilage damage score (CDS) relative to the contralateral control knee for each compartment as well as for the whole knee, pooled by meniscal treatment, while controlling for sex, age, body mass index, baseline Marx activity score, and baseline operative cartilage grade. For analysis, meniscal injuries surgically treated with partial meniscectomy or meniscal repair were grouped together. RESULTS: The cohort included 60 patients (32 female; median age, 18.7 years). Concomitant meniscal treatment at the time of index ACLR was performed in 17 medial menisci (13 meniscal repair and 4 partial meniscectomy) and 27 lateral menisci (3 meniscal repair and 24 partial meniscectomy). Articular cartilage damage was worse in the ipsilateral reconstructed knee (P < .001). A meniscal injury requiring surgical treatment with ACLR predicted a worse CDS for medial meniscal treatment (medial compartment CDS: P = .005; whole joint CDS: P < .001) and lateral meniscal treatment (lateral compartment CDS: P = .038; whole joint CDS: P = .863). Other predictors of a worse relative CDS included age for the medial compartment (P < .001), surgically observed articular cartilage damage for the patellofemoral compartment (P = .048), and body mass index (P = .007) and age (P = .020) for the whole joint. CONCLUSION: A meniscal injury requiring surgical treatment with partial meniscectomy or meniscal repair at the time of ACLR predicted worse articular cartilage damage on MRI at 2 to 3 years after surgery. Further research is required to differentiate between the effects of partial meniscectomy and meniscal repair.

Effect of Baseline Mental Health on 1-Year Outcomes After Hip Arthroscopy: A Prospective Cohort Study.

BACKGROUND: Patient factors, including mental health, sex, and smoking, have been found to be more predictive of preoperative hip pain and function than intra-articular findings during hip arthroscopy for femoroacetabular impingement (FAI); however, little is known about how these factors may influence patients' postoperative outcomes. HYPOTHESIS: We hypothesized that lower patient-reported mental health scores would be significant risk factors for worse patient-reported outcomes (PROs) 1 year after arthroscopic hip surgery for FAI and that baseline intra-articular pathology would fail to demonstrate an association with outcomes 1 year after FAI surgery. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A prospective cohort of patients undergoing hip arthroscopy for FAI were electronically enrolled. Baseline and 1-year follow-up PROs were collected, including Hip disability and Osteoarthritis Outcome Score for pain (HOOS-Pain), HOOS-Physical Function Short Form (HOOS-PS), and Veterans RAND 12-Item Health Survey-Mental Component Score (VR-12 MCS). Intra-articular operative findings and treatment were documented at the time of surgery. Proportional odds logistic regression models were built for 1-year outcomes (HOOS-Pain, HOOS-PS, and VR-12 MCS). Risk factors included patient characteristics and intraoperative anatomic and pathologic findings. RESULTS: Overall, 494 patients underwent hip arthroscopy for FAI, and 385 (78%) were evaluated at 1 year with at least 1 PRO. The median patient age was 33 years, mean body mass index was 25.5 kg/m2, and 72% were female. Multivariable analysis demonstrated that better baseline HOOS-Pain, HOOS-PS, and VR-12 MCS were significantly associated with improvement in the 1-year scores for each PRO. Higher VR-12 MCS was significantly associated with better 1-year HOOS-Pain and HOOS-PS, while current and former smokers had worse 1-year outcomes than those who never smoked. In ranking each variable's relative importance, baseline HOOS-Pain and HOOS-PS and baseline VR-12 MCS were identified as the strongest predictors of 1-year HOOS-Pain and HOOS-PS in our multivariable model. CONCLUSION: During hip arthroscopy for FAI, patient factors, including baseline hip pain and function, mental health, and smoking, were independently associated with 1-year PROs of hip pain and function, while intra-articular pathology such as the presence of labral tear and its treatment, tear size, tear location, and anchors placed were not independently associated.

Do Narcotic Use, Physical Therapy Location, or Payer Type Predict Patient-Reported Outcomes After Anterior Cruciate Ligament Reconstruction?

BACKGROUND: Opioid use and public insurance have been correlated with worse outcomes in a number of orthopaedic surgeries. These factors have not been investigated with anterior cruciate ligament reconstruction (ACLR). PURPOSE/HYPOTHESIS: To evaluate if narcotic use, physical therapy location, and insurance type are predictors of patient-reported outcomes after ACLR. It was hypothesized that at 1 year postsurgically, increased postoperative narcotic use would be associated with worse outcomes, physical therapy obtained within the authors' integrated health care system would lead to better outcomes, and public insurance would lead to worse outcomes and athletic activity. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: All patients undergoing unilateral, primary ACLR between January 2015 and February 2016 at a large health system were enrolled in a standard-of-care prospective cohort. Knee injury and Osteoarthritis Score (KOOS) and the Hospital for Special Surgery Pediatric-Functional Activity Brief Scale (HSS Pedi-FABS) were collected before surgery and at 1 year postoperatively. Concomitant knee pathology was assessed arthroscopically and electronically captured. Patient records were analyzed to determine physical therapy location, insurance status, and narcotic use. Multivariable regression analyses were used to identify significant predictors of the KOOS and HSS Pedi-FABS score. RESULTS: A total of 258 patients were included in the analysis (mean age, 25.8; 51.2% women). In multivariable regression analysis, narcotic use, physical therapy location, and insurance type were not independent predictors of any KOOS subscales. Public insurance was associated with a lower HSS Pedi-FABS score (-4.551, P = .047) in multivariable analysis. Narcotic use or physical therapy location was not associated with the HSS Pedi-FABS score. CONCLUSION: Increased narcotic use surrounding surgery, physical therapy location within the authors' health care system, and public versus private insurance were not associated with disease-specific KOOS subscale scores. Patients with public insurance had worse HSS Pedi-FABS activity scores compared with patients with private insurance, but neither narcotic use nor physical therapy location was associated with activity scores. Physical therapy location did not influence outcomes, suggesting that patients be given a choice in the location they received physical therapy (as long as a standardized protocol is followed) to maximize compliance.

Measuring Outcomes in Knee Articular Cartilage Pathology.

Measuring outcomes following treatment of knee articular cartilage lesions is crucial to determine the natural history of disease and the efficacy of treatments. Outcome assessments for articular cartilage treatments can be clinical (based on failure, lack of healing, reoperation, need for arthroplasty), radiographic (X-ray, MRI), histologic, or patient reported and functional. The purpose of this review is to discuss the application and properties of patient-reported outcomes (PROs) with a focus on articular cartilage injuries and surgery in the knee. The most frequently used and validated PROs for knee articular cartilage studies include: the Knee injury and Osteoarthritis and Outcome Score, International Knee Documentation Committee Subjective Knee Form, and Lysholm score as knee-specific measures; the Marx Activity Rating Scale and Tegner Activity Scale as activity measures; and EQ-5D and SF-36/12 as generic quality-of-life measures. Incorporating these validated PROs in studies pertaining to knee articular cartilage lesions will allow researchers to fully capture clinically relevant outcomes that are most important to patients.

Smartphone Data Capture Efficiently Augments Dictation for Knee Arthroscopic Surgery.

INTRODUCTION: The objectives of this study are (1) to develop a provider-friendly, evidence-based data capture system for lower-limb orthopaedic surgeries and (2) to assess the performance of the data capture system on the dimensions of agreement with operative note and implant log, consistency of data, and speed of provider input. METHODS: A multidisciplinary team developed a database and user interfaces for Android and iOS operating systems. Branching logic and discrete fields were created to streamline provider data input. One hundred patients were randomly selected from the first four months of data collection (February to June 2015). Patients were limited to those undergoing anterior cruciate ligament reconstruction, meniscal repair, partial meniscectomy, or a combination of these procedures. Duplicate data on these 100 patients were collected through chart review. These two data sets were compared. Cohen's kappa statistic was used to assess agreement. RESULTS: The database and smartphone data capture tool show almost perfect agreement (kappa > 0.81) for all data tested. In addition, data are more comprehensive with near-perfect provider completion (100% for all data tested). Furthermore, provider data entry is extremely efficient (median 151-second completion time). CONCLUSION: A well-designed database and user-friendly interface have greater potential for research utility, clinical efficiency, and, thus, cost-effectiveness when compared with standard voice-dictated operative notes. Widespread utilization of such tools can accelerate the pace and improve the quality of orthopaedic clinical research. LEVEL OF EVIDENCE: Level IV.

Predictors of Radiographic Osteoarthritis 2 to 3 Years After Anterior Cruciate Ligament Reconstruction: Data From the MOON On-site Nested Cohort.

BACKGROUND: Multiple studies have shown that patients are susceptible to posttraumatic osteoarthritis (PTOA) after an anterior cruciate ligament (ACL) injury, even with ACL reconstruction (ACLR). Prospective studies using multivariable analysis to identify risk factors for PTOA are lacking. PURPOSE/HYPOTHESIS: This study aimed to identify baseline predictors of radiographic PTOA after ACLR at an early time point. We hypothesized that meniscal injuries and cartilage lesions would be associated with worse radiographic PTOA using the Osteoarthritis Research Society International (OARSI) atlas criteria. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 421 patients who underwent ACLR returned on-site for standardized posteroanterior semiflexed knee radiography at a minimum of 2 years after surgery. The mean age was 19.8 years, with 51.3% female patients. At baseline, data on demographics, graft type, meniscal status/treatment, and cartilage status were collected. OARSI atlas criteria were used to grade all knee radiographs. Multivariable ordinal regression models identified baseline predictors of radiographic OARSI grades at follow-up. RESULTS: Older age (odds ratio [OR], 1.06) and higher body mass index (OR, 1.05) were statistically significantly associated with a higher OARSI grade in the medial compartment. Patients who underwent meniscal repair and partial meniscectomy had statistically significantly higher OARSI grades in the medial compartment (meniscal repair OR, 1.92; meniscectomy OR, 2.11) and in the lateral compartment (meniscal repair OR, 1.96; meniscectomy OR, 2.97). Graft type, cartilage lesions, sex, and Marx activity rating scale score had no significant association with the OARSI grade. CONCLUSION: Older patients with a higher body mass index who have an ACL tear with a concurrent meniscal tear requiring partial meniscectomy or meniscal repair should be advised of their increased risk of developing radiographic PTOA. Alternatively, patients with an ACL tear with an articular cartilage lesion can be reassured that they are not at an increased risk of developing early radiographic knee PTOA at 2 to 3 years after ACLR.

Birmingham hip resurfacing versus cementless total hip arthroplasty in patients 55 years or younger: A minimum five-year follow-up.

OBJECTIVE: The optimal reconstructive method for advanced degenerative hip disease in young adults is a topic of ongoing discussion. The purpose of this study is to report the largest single institution experience from the United States on the outcomes of Birmingham hip resurfacing (BHR) vs. cementless total hip arthroplasty (THA) in patients 55 years or younger at a minimum follow-up of five years. Currently, BHR is the only FDA-approved hip resurfacing implant available in the US. METHODS: A cohort of 505 patients representing all BHR cases performed at our institution between 2006 and 2010 was compared with an identical size cohort of consecutive patients who underwent primary cementless THA. Exclusion criteria were age greater than 55 years, non-elective cases, revision procedures, and those performed for fractures, tumors, or by low-volume arthroplasty surgeons. THAs with metal on metal articulation were also excluded. OUTCOMES: assessed were all-cause reoperations, complications, patient satisfaction, and mortality. After exclusions, 442 patients with BHR and 327 with THA were included. RESULTS: Mean follow-up was 73.2 months. After controlling for potential confounding factors, multivariate analyses showed significant increase in the rates of revision surgery (p < 0.001), overall complications (p < 0.001), all-cause reoperations (p = 0.014), and mortality (p < 0.001) in the THA cohort. Component loosening was the most common cause for revision in the THA group. Patients with THA were also less likely to be satisfied (p = 0.046). CONCLUSIONS: This is largest US study to report on the midterm outcomes of BHR vs. THA. The results demonstrate favorable results for BHR in patients 55 years or younger. Long-term multicenter studies are needed to better understand the optimal patient characteristics when deciding between THA versus BHR.

Mid-Term Results and Predictors of Patient-Reported Outcomes of Birmingham Hip Resurfacing.

BACKGROUND: Birmingham hip resurfacing (BHR) is the only Food and Drug Administration approved resurfacing option currently available in the United States. While adequate BHR outcomes are established, there is a paucity of US-based literature demonstrating factors critical to improve patient reported outcomes (PROs). This study answers: (1) What is the implant survivorship in a large US cohort? (2) Which preoperative factors result in higher PRO scores over 5 years postoperatively? METHODS: A retrospective 541 hip single-surgeon cohort with mean of 6.2 years follow-up (range 5-8.1) was collected. Preoperative patient/implant variables, including postoperative radiographic acetabular inclination and femoral component position, clinical outcomes, and follow-up PRO questionnaire information were collected. Validated PROs included the Hip Disability and Osteoarthritis Outcome Score (HOOS), Veterans Rand-12, and University of California Los Angeles (UCLA) activity. PROs were modeled with ordinary least squares then used to create nomograms. RESULTS: Average patient age was 53 years with 391 (72%) males. Seven hips were revised, resulting in an overall survival of 98.8% at 5 years. Predictive modeling identified preoperative variables (sex, body mass index, smoking, and comorbidity) that had statistically significant associations with HOOS pain (P = .049), HOOS activities of daily living (P = .017), UCLA activity (P < .001), and Veterans Rand-12 physical (P < .001) PROs at latest follow-up. Nomograms predicted follow-up PROs using preoperative patient-specific variables. CONCLUSION: This study documents excellent survival of the largest reported single-center cohort of BHRs in the United States with a mean 6.2 years follow-up. Multivariate modeling shows male nonsmokers with low body mass index, and no comorbidities will have less hip pain, better function in daily life, higher activity, and better general physical health after BHR arthroplasty.

Adolescent Femoroacetabular Impingement: Gender Differences in Hip Morphology.

PURPOSE: To compare the hip morphology of adolescent male patients and female patients who underwent hip arthroscopy for femoroacetabular impingement (FAI) and determine if gender differences exist. METHODS: We retrospectively reviewed the records of 177 adolescents, aged 13 to 18 years, who were treated for FAI with hip arthroscopy. We examined and analyzed preoperative magnetic resonance imaging (MRI) scans and plain radiographs, measuring the lateral center-edge angle, Tönnis angle, and alpha angle. The intraclass correlation coefficient between readers was calculated. We created multiple linear regression models incorporating age, gender, and body mass index (BMI) with the radiographic measurements. Intraoperative findings using the Outerbridge grading system, as well as procedure performed, were documented. We compared these findings with our preoperative imaging measurements using the χ2 test and the Wilcoxon rank sum test. RESULTS: The intraclass correlation coefficient showed moderate to strong agreement between the 3 image readers. The BMI- and age-adjusted mean alpha angle was higher in male patients than female patients on both plain radiographs (55.9° vs 45.2°, P < .0001) and axial oblique MRI scans (54.1° vs 42.5°, P < .0001). An alpha angle greater than 55° was found in 38.9% of male patients compared with only 1% of female patients (P < .0001). The lateral center-edge angle and Tönnis angle on MRI scans and plain radiographs displayed no statistically significant differences between genders after we controlled for BMI and age. Male patients were more likely to have chondral damage intraoperatively than female patients (56.3% vs 32.5%, P = .0041). CONCLUSIONS: Distinct differences between genders were seen both on preoperative imaging and at the time of hip arthroscopy. We found that male patients with FAI displayed a larger mean alpha angle, and therefore a more severe cam-type deformity, than female patients. Our study also found that male patients were more likely to show evidence of chondral damage than female patients at the time of surgery. LEVEL OF EVIDENCE: Level IV.

Targeting interleukin-13 with tralokinumab attenuates lung fibrosis and epithelial damage in a humanized SCID idiopathic pulmonary fibrosis model.

The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung.

A micro RNA processing defect in rapidly progressing idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF. METHODOLOGY AND PRINCIPAL FINDINGS: miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts. CONCLUSION: These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing.

TLR9 differentiates rapidly from slowly progressing forms of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is characterized by diffuse alveolar damage and severe fibrosis, resulting in a steady worsening of lung function and gas exchange. Because idiopathic pulmonary fibrosis is a generally progressive disorder with highly heterogeneous disease progression, we classified affected patients as either rapid or slow progressors over the first year of follow-up and then identified differences between the two groups to investigate the mechanism governing rapid progression. Previous work from our laboratory has demonstrated that Toll-like receptor 9 (TLR9), a pathogen recognition receptor that recognizes unmethylated CpG motifs in bacterial and viral DNA, promotes myofibroblast differentiation in lung fibroblasts cultured from biopsies of patients with idiopathic pulmonary fibrosis. Therefore, we hypothesized that TLR9 functions as both a sensor of pathogenic molecules and a profibrotic signal in rapidly progressive idiopathic pulmonary fibrosis. Indeed, TLR9 was present at higher concentrations in surgical lung biopsies from rapidly progressive patients than in tissue from slowly progressing patients. Moreover, fibroblasts from rapid progressors were more responsive to the TLR9 agonist, CpG DNA, than were fibroblasts from slowly progressing patients. Using a humanized severe combined immunodeficient mouse, we then demonstrated increased fibrosis in murine lungs receiving human lung fibroblasts from rapid progressors compared with mice receiving fibroblasts from slowly progressing patients. This fibrosis was exacerbated by intranasal CpG challenges. Furthermore, CpG induced the differentiation of blood monocytes into fibrocytes and the epithelial-to-mesenchymal transition of A549 lung epithelial cells. These data suggest that TLR9 may drive the pathogenesis of rapidly progressive idiopathic pulmonary fibrosis and may serve as a potential indicator for this subset of the disease.

Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages.

BACKGROUND: Interleukin-33 is a member of the IL-1 cytokine family whose functions are mediated and modulated by the ST2 receptor. IL-33-ST2 expression and interactions have been explored in mouse macrophages but little is known about the effect of IL-33 on human macrophages. The expression of ST2 transcript and protein levels, and IL-33-mediated effects on M1 (i.e. classical activation) and M2 (i.e. alternative activation) chemokine marker expression in human bone marrow-derived macrophages were examined. RESULTS: Human macrophages constitutively expressed the membrane-associated (i.e. ST2L) and the soluble (i.e. sST2) ST2 receptors. M2 (IL-4 + IL-13) skewing stimuli markedly increased the expression of ST2L, but neither polarizing cytokine treatment promoted the release of sST2 from these cells. When added to naïve macrophages alone, IL-33 directly enhanced the expression of CCL3. In combination with LPS, IL-33 blocked the expression of the M2 chemokine marker CCL18, but did not alter CCL3 expression in these naive cells. The addition of IL-33 to M1 macrophages markedly increased the expression of CCL18 above that detected in untreated M1 macrophages. Similarly, alternatively activated human macrophages treated with IL-33 exhibited enhanced expression of CCL18 and the M2 marker mannose receptor above that detected in M2 macrophages alone. CONCLUSIONS: Together, these data suggest that primary responses to IL-33 in bone marrow derived human macrophages favors M1 chemokine generation while its addition to polarized human macrophages promotes or amplifies M2 chemokine expression.