Processes of sterile inflammation Shen, Hua; Kreisel, Daniel; Goldstein, Daniel Robert
The Journal of immunology (1950),
2013-Sep-15, Letnik:
191, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Sterile inflammation occurs in acute conditions, such as ischemia reperfusion injury and crystal-induced arthritis, as well as with chronic diseases, such as particle-induced lung diseases and ...atherosclerosis. The triggers of sterile inflammation are still being identified, and the pathways that transduce sterile inflammatory signals are not completely clear. Most of the innate immune pathways that sense infection have been implicated in sterile inflammation, although distinct signaling pathways of sterile inflammation exist. Whether immune pathology ensues after sterile inflammation depends on the balance of induced inflammatory and resolution pathways. Further identification of the molecular mechanisms of sterile inflammation will lead to novel therapeutics to treat a range of diseases.
Recent advancements have brought to light the origins, complexity, and functions of tissue-resident macrophages. However, in the context of tissue injury or disease, large numbers of monocytes ...infiltrate the heart and are thought to contribute to adverse remodeling and heart failure pathogenesis. Little is understood about the diversity of monocytes and monocyte-derived macrophages recruited to the heart after myocardial injury, including the mechanisms that regulate monocyte recruitment and fate specification.
We sought to test the hypothesis that distinct subsets of tissue-resident CCR2- (C-C chemokine receptor 2) and CCR2+ macrophages orchestrate monocyte recruitment and fate specification after myocardial injury.
We reveal that in numerous mouse models of cardiomyocyte cell death (permanent myocardial infarction, reperfused myocardial infarction, and diphtheria toxin cardiomyocyte ablation), there is a shift in macrophage ontogeny whereby tissue-resident macrophages are predominately replaced by infiltrating monocytes and monocyte-derived macrophages. Using syngeneic cardiac transplantation to model ischemia-reperfusion injury and distinguish tissue-resident from recruited cell populations in combination with intravital 2-photon microscopy, we demonstrate that monocyte recruitment is differentially orchestrated by distinct subsets of tissue-resident cardiac macrophages. Tissue-resident CCR2+ macrophages promote monocyte recruitment through an MYD88 (myeloid differentiation primary response 88)-dependent mechanism that results in release of MCPs (monocyte chemoattractant proteins) and monocyte mobilization. In contrast, tissue-resident CCR2- macrophages inhibit monocyte recruitment. Using CD (cluster of differentiation) 169-DTR (diphtheria toxin receptor) and CCR2-DTR mice, we further show that selective depletion of either tissue-resident CCR2- or CCR2+ macrophages before myocardial infarction results in divergent effects on left ventricular function, myocardial remodeling, and monocyte recruitment. Finally, using single-cell RNA sequencing, we show that tissue-resident cardiac macrophages differentially instruct monocyte fate specification.
Collectively, these observations establish the mechanistic basis by which monocytes are initially recruited to the injured heart and provide new insights into the heterogeneity of monocyte-derived macrophages.
Conflicting evidence currently exists regarding the causes and effects of delay of care in non-small cell lung cancer (NSCLC). We hypothesized that delayed surgery in early-stage NSCLC is associated ...with worse short-term and long-term outcomes.
Treatment data of clinical stage I NSCLC patients undergoing surgical resection were obtained from the National Cancer Data Base (NCDB). Treatment delay was defined as resection 8 weeks or more after diagnosis. Propensity score matching for patient and tumor characteristics was performed to create comparable groups of patients receiving early (less than 8 weeks from diagnosis) and delayed surgery. Multivariable regression models were fitted to evaluate variables influencing delay of surgery.
From 1998 to 2010, 39,995 patients with clinical stage I NSCLC received early surgery, while 15,658 patients received delayed surgery. Of these, 27,022 propensity-matched patients were identified. Those with a delay in care were more likely to be pathologically upstaged (18.3% stage 2 or higher versus 16.6%, p < 0.001), have an increased 30-day mortality (2.9% vs 2.4%, p = 0.01), and have decreased median survival (57.7 ± 1.0 months versus 69.2 ± 1.3 months, p < 0.001). Delay in surgery was associated with increasing age, non-white race, treatment at an academic center, urban location, income less than $35,000, and increasing Charlson comorbidity score (p < 0.0001 for all). Delayed patients were more likely to receive a sublobar resection (17.2% vs 13.1%, p < 0.001).
Patients receiving delayed resection for clinical stage I NSCLC have higher comorbidity scores that may affect ability to perform lobectomy and result in higher perioperative mortality. However, delay in resection is independently associated with increased rates of upstaging and decreased median survival. Strategies to minimize delay while medically optimizing higher risk patients are needed.
Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years ...of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of coronary artery ligation-induced myocardial ischemia reperfusion injury where inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular systolic function, and reduced left ventricular remodeling. Using intravital imaging of cardiac transplants, we uncover that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/TRIF/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients, who are vulnerable to ischemia reperfusion injury following restoration of coronary blood flow.
Acute lung injury (ALI) is a heterogeneous inflammatory condition associated with high morbidity and mortality. Neutrophils play a key role in the development of different forms of ALI, and the ...release of neutrophil extracellular traps (NETs) is emerging as a common pathogenic mechanism. NETs are essential in controlling pathogens, and their defective release or increased degradation leads to a higher risk of infection. However, NETs also contain several pro-inflammatory and cytotoxic molecules than can exacerbate thromboinflammation and lung tissue injury. To reduce NET-mediated lung damage and inflammation, DNase is frequently used in preclinical models of ALI due to its capability of digesting NET DNA scaffold. Moreover, recent advances in neutrophil biology led to the development of selective NET inhibitors, which also appear to reduce ALI in experimental models. Here we provide an overview of the role of NETs in different forms of ALI discussing existing gaps in our knowledge and novel therapeutic approaches to modulate their impact on lung injury.
Summary
Solid organ transplantation is a vital therapy for end stage diseases. Decades of research have established that components of the adaptive immune system are critical for transplant ...rejection, but the role of the innate immune system in organ transplantation is just emerging. Accumulating evidence indicates that the innate immune system is activated at the time of organ implantation by the release of endogenous inflammatory triggers. This review discusses the nature of these triggers in organ transplantation and also potential mediators that may enhance inflammation resolution after organ implantation.
Objectives Stereotactic body radiation therapy has been proposed as an alternative local treatment option for high-risk patients with early-stage lung cancer. A direct comparison of outcomes between ...stereotactic body radiation therapy and surgical resection has not been reported. This study compares short-term outcomes between stereotactic body radiation therapy and surgical treatment of non–small cell lung cancer. Methods We compared all patients treated with surgery (January 2000–December 2006) or stereotactic body radiation therapy (February 2004–May 2007) with clinical stage IA/B non–small cell lung cancer staged by computed tomography and positron emission tomography. Comorbidity scores were recorded prospectively using the Adult Co-Morbidity Evaluation scoring system. Charts were reviewed to determine local tumor recurrence, disease-specific survival, and overall survival. A propensity score matching analysis was used to adjust estimated treatment hazard ratios for confounding effects of patient age, comorbidity index, and clinical stage. Results A total of 462 patients underwent surgery and 76 received stereotactic body radiation therapy. Overall, surgical patients were younger ( P < .001), had lower comorbidity scores ( P < .001), and better pulmonary function (forced expiratory volume in 1 second and carbon monoxide diffusion in the lung) ( P < .001). Among the surgical and stereotactic body radiation therapy groups, 62.6% (291/462) and 78.9% (60/76) were in clinical stage IA, respectively. Final pathology upstaged 35% (161/462) of the surgery patients. In an unmatched comparison, overall 5-year survival was 55% with surgery, and the 3-year survival was 32% with radiation therapy. Among patients with clinical stage IA disease, 3-year local tumor control was 89% with radiation therapy and 96% with surgery ( P = .04). There was no difference in local tumor control in stage IB disease ( P = .89). No disease-specific survival differences were found in patients with 1A ( P = .33) or IB disease ( P = .69). Propensity analysis matched 57 high-risk surgical patients to 57 patients undergoing stereotactic body radiation therapy. In the matched comparison of this subgroup, there was no difference in freedom from local recurrence (88% vs 90%), disease-free survival (77% vs 86%), and overall survival (54% vs 38%) at 3 years. Conclusions In an unmatched comparison of clinical stage IA disease, surgical patients were healthier and had better local tumor control compared with those receiving stereotactic body radiation therapy. Propensity analysis in clinical stage IA/B non–small cell lung cancer revealed similar rates of local recurrence and disease-specific survival in patients treated with surgery compared with stereotactic body radiation therapy.
Objective To study causes and implications of intraoperative conversion to thoracotomy during video-assisted thoracoscopic surgery (VATS) lobectomy. Methods We performed an institutional review of ...patients undergoing lobectomy for known or suspected lung cancer with root cause analysis of every conversion from VATS to open thoracotomy. Results Between 2004 and 2012, 1227 patients underwent lobectomy. Of these, 517 procedures (42%) were completed via VATS, 87 procedures (7%) were converted to open procedures, and 623 procedures (51%) were performed via planned thoracotomy. Patients undergoing thoracotomy were younger and had a higher incidence of prior lung cancers. Planned thoracotomy and conversion group patients had higher clinical T stage than patients in the VATS group, whereas the planned thoracotomy group had higher pathologic stage than patients in the other groups. Postoperative complications were more frequent in patients in the conversion group (46%) than in the VATS group (23%; P < .001), but similar to the open group (42%; P = .56). Validating a previous classification of causes for conversion, 22 out of 87 conversions (25%) were due to vascular causes, 56 conversions (64%) were for anatomy (eg, adhesions or tumor size), and 8 conversions (9%) were the result of lymph nodes. No specific imaging variables predicted conversion. Within the conversion groups, emergent (20 out of 87; 23%) and planned (67 out of 87; 77%) conversion groups were similar in patient and tumor characteristics and incidence of perioperative morbidity. The conversion rate for VATS lobectomy dropped from 21 out of 74 (28%), to 29 out of 194 (15%), to 37 out of 336 (11%) ( P < .001) over 3-year intervals. Over the same periods, the proportion of operations started via VATS increased significantly. Conclusions With increasing experience, a higher proportion of lobectomy operations can be completed thoracoscopically. VATS should be strongly considered as the initial approach for the majority of patients undergoing lobectomy.
Paradigm shifting studies have revealed that the heart contains functionally diverse populations of macrophages derived from distinct embryonic and adult hematopoietic progenitors. Under steady-state ...conditions, the heart is largely populated by CCR2- (C-C chemokine receptor type 2) macrophages of embryonic descent. After tissue injury, a dramatic shift in macrophage composition occurs whereby CCR2+ monocytes are recruited to the heart and differentiate into inflammatory CCR2+ macrophages that contribute to heart failure progression. Currently, there are no techniques to noninvasively detect CCR2+ monocyte recruitment into the heart and thus identify patients who may be candidates for immunomodulatory therapy.
To develop a noninvasive molecular imaging strategy with high sensitivity and specificity to visualize inflammatory monocyte and macrophage accumulation in the heart.
We synthesized and tested the performance of a positron emission tomography radiotracer (
Ga-DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-ECL1i extracellular loop 1 inverso) that allosterically binds to CCR2. In naive mice, the radiotracer was quickly cleared from the blood and displayed minimal retention in major organs. In contrast, biodistribution and positron emission tomography demonstrated strong myocardial tracer uptake in 2 models of cardiac injury (diphtheria toxin induced cardiomyocyte ablation and reperfused myocardial infarction).
Ga-DOTA-ECL1i signal localized to sites of tissue injury and was independent of blood pool activity as assessed by quantitative positron emission tomography and ex vivo autoradiography.
Ga-DOTA-ECL1i uptake was associated with CCR2+ monocyte and CCR2+ macrophage infiltration into the heart and was abrogated in CCR2
mice, demonstrating target specificity. Autoradiography demonstrated that
Ga-DOTA-ECL1i specifically binds human heart failure specimens and with signal intensity associated with CCR2+ macrophage abundance.
These findings demonstrate the sensitivity and specificity of
Ga-DOTA-ECL1i in the mouse heart and highlight the translational potential of this agent to noninvasively visualize CCR2+ monocyte recruitment and inflammatory macrophage accumulation in patients.
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