Endotracheal tube-induced sore throat pain and inflammation is coupled to the release of mitochondrial DNA

In the absence of infection, the pathophysiology of endotracheal tube-induced sore throat pain is unclear. Activated neutrophils release elastase, reactive oxygen species, and inflammatory cytokines known to contribute to neuropathic pain. Sterile tissue injury can cause the release of damage-associated molecular patterns such as mitochondrial DNA that promote neutrophil activation. We hypothesized that endotracheal tube-induced sore throat pain is linked to mitochondrial DNA-mediated neutrophil inflammation. A nonrandomized prospective survey for sore throat pain was conducted in 31 patients who required short-term intubation and had no evidence of upper airway infection. Patterns of neutrophil abundance, activation, and mitochondrial DNA levels were analyzed in tracheal lavage fluid following intubation and prior to extubation. Thirteen of 31 patients reported sore throat pain. Sore throat patients had high neutrophilia with elevated adhesion molecule and TLR9 expression and constitutive reactive oxygen species generation. Tracheal lavage fluid from sore throat patients accumulated mitochondrial DNA and stimulated neutrophils to release mediators associated with pain in a TLR9- and DNAse-dependent fashion. Endotracheal tube-induced sore throat is linked to the release of mitochondrial DNA and can drive TLR9-mediated inflammatory responses by neutrophils reported to cause pain. Mitigating the effects of cell-free mitochondrial DNA may prove beneficial for the prevention of endotracheal tube-mediated sore throat pain

Single-Lung Transplantation in the Setting of Aborted Bilateral Lung Transplantation

Background. The outcome of patients undergoing a single-lung transplant in the setting of an aborted bilateral lung transplant is unclear. Methods. A retrospective review of single lung transplants at an institutional program. Results. Of the 543 lung transplants performed over the last 10 years, 31 (5.7%) were single-lung transplants. Nineteen of 31 (61%) were planned single-lung transplants, while 12/31 (39%) were intraoperatively aborted, double lung transplants converted to single-lung transplants. The aborted and planned groups were similar in age, lung allocation score and NYHA status. The reasons for aborted double lung transplantation were cardiac/hemodynamic instability 4/12 (33%), difficult pneumonectomy 3/12 (25%), size mismatch 4/12(33%), and technical issues 1/12 (8%). The aborted group had higher CPB utilization (5/12 versus 1/19, P = .02), similar ischemic times (260 versus 234 min) and similar incidence of grade 3 primary graft dysfunction (6/12 versus 3/19, P = .13). ECMO was required for graft dysfunction in 2 patients in the aborted group. The one and two-year survival was 84% and 79% in the planned group and 62% and 52% in the aborted group, respectively. Conclusions. Patients undergoing single-lung transplantation in the setting of an aborted bilateral lung transplant may be at a higher risk of worse outcomes

The role of neutrophil extracellular traps in acute lung injury

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

Unique pulmonary antigen presentation may call for an alternative approach toward lung cancer immunotherapy

Unlike other tumors, lung cancer appears to be poorly sensitive to immunotherapy. We have recently demonstrated an alternative pathway of lung cancer immunosurveillance. Our data indicate a failure of the adaptive immune system to mediate the immunosurveillance of lung cancer and emphasize the prominent role of natural killer cells in this setting

A thoracic surgery clinic dedicated to indeterminate pulmonary nodules: Too many scans and too little pathology?

ObjectiveWidespread application of computed tomographic scans has increased detection of asymptomatic pulmonary nodules. A dedicated clinic was established to encourage referral and manage large numbers of patients with such nodules.MethodsPatients were evaluated periodically by a nurse practitioner with surgeon oversight, and follow-up imaging was centralized. Patients were rescanned at intervals on the basis of radiologist recommendation.ResultsA total of 414 patients, 189 male and 225 female with a median age of 60.2 years (20.7–84.1 years), were evaluated since April 2000. Median follow-up was 1.51 years (0–6.65 years). Thirty-seven percent (153/414) were older than 60 years with at least 10 pack-years of tobacco use, whereas 30% (123/414) had never smoked. A total of 286 patients completed at least 2 years of follow-up computed tomographic evaluation. After 2 years, 24.2% (69/286) were deemed in stable condition and were discharged from further follow-up, whereas 22.4% (64/286) of patients were followed up longer than 2 years owing to the development of new nodules. Forty-five percent (127/286) of patients did not complete their recommended follow-up at our clinic. Overall, 3% (13/414) of our patients have been shown to have a malignant tumor. Only 5 patients underwent curative resection of a primary lung cancer.ConclusionIn a population of patients with indeterminate nodules in routine clinical practice, few patients required intervention and few cancers were detected. Although the benefits of a “nodule” clinic may include patient reassurance and convenience to referring physicians, a significant number of patients did not complete their follow-up in our clinic

Clinical Study Single-Lung Transplantation in the Setting of Aborted Bilateral Lung Transplantation

Background. The outcome of patients undergoing a single-lung transplant in the setting of an aborted bilateral lung transplant is unclear. Methods. A retrospective review of single lung transplants at an institutional program. Results. Of the 543 lung transplants performed over the last 10 years, 31 (5.7%) were single-lung transplants. Nineteen of 31 (61%) were planned singlelung transplants, while 12/31 (39%) were intraoperatively aborted, double lung transplants converted to single-lung transplants. The aborted and planned groups were similar in age, lung allocation score and NYHA status. The reasons for aborted double lung transplantation were cardiac/hemodynamic instability 4/12 (33%), difficult pneumonectomy 3/12 (25%), size mismatch 4/12(33%), and technical issues 1/12 (8%). The aborted group had higher CPB utilization (5/12 versus 1/19, P = .02), similar ischemic times (260 versus 234 min) and similar incidence of grade 3 primary graft dysfunction (6/12 versus 3/19, P = .13). ECMO was required for graft dysfunction in 2 patients in the aborted group. The one and two-year survival was 84% and 79% in the planned group and 62% and 52% in the aborted group, respectively. Conclusions. Patients undergoing single-lung transplantation in the setting of an aborted bilateral lung transplant may be at a higher risk of worse outcomes

Surgical technique for lung retransplantation in the mouse

Microsurgical cuff techniques for orthotopic vascularized murine lung transplantation have allowed for the design of studies that examine mechanisms contributing to the high failure rate of pulmonary grafts. Here, we provide a detailed technical description of orthotopic lung retransplantation in mice, which we have thus far performed in 144 animals. The total time of the retransplantation procedure is approximately 55 minutes, 20 minutes for donor harvest and 35 minutes for the implantation, with a success rate exceeding 95%. The mouse lung retransplantation model represents a novel and powerful tool to examine how cells that reside in or infiltrate pulmonary grafts shape immune responses

Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis

Granulocytes are pivotal regulators of tissue injury. However, the transcriptional mechanisms that regulate granulopoiesis under inflammatory conditions are poorly understood. Here we show that the transcriptional coregulator B cell leukemia/lymphoma 3 (Bcl3) limits granulopoiesis under emergency (i.e., inflammatory) conditions, but not homeostatic conditions. Treatment of mouse myeloid progenitors with G-CSF — serum concentrations of which rise under inflammatory conditions — rapidly increased Bcl3 transcript accumulation in a STAT3-dependent manner. Bcl3-deficient myeloid progenitors demonstrated an enhanced capacity to proliferate and differentiate into granulocytes following G-CSF stimulation, whereas the accumulation of Bcl3 protein attenuated granulopoiesis in an NF-κB p50–dependent manner. In a clinically relevant model of transplant-mediated lung ischemia reperfusion injury, expression of Bcl3 in recipients inhibited emergency granulopoiesis and limited acute graft damage. These data demonstrate a critical role for Bcl3 in regulating emergency granulopoiesis and suggest that targeting the differentiation of myeloid progenitors may be a therapeutic strategy for preventing inflammatory lung injury

The role of neutrophil extracellular traps in acute lung injury

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