Prolonged dialysis during ex vivo lung perfusion promotes inflammatory responses.

Ex-vivo lung perfusion (EVLP) has extended the number of transplantable lungs by reconditioning marginal organs. However, EVLP is performed at 37°C without homeostatic regulation leading to metabolic wastes' accumulation in the perfusate and, as a corrective measure, the costly perfusate is repeatedly replaced during the standard of care procedure. As an interesting alternative, a hemodialyzer could be placed on the EVLP circuit, which was previously shown to rebalance the perfusate composition and to maintain lung function and viability without appearing to impact the global gene expression in the lung. Here, we assessed the biological effects of a hemodialyzer during EVLP by performing biochemical and refined functional genomic analyses over a 12h procedure in a pig model. We found that dialysis stabilized electrolytic and metabolic parameters of the perfusate but enhanced the gene expression and protein accumulation of several inflammatory cytokines and promoted a genomic profile predicting higher endothelial activation already at 6h and higher immune cytokine signaling at 12h. Therefore, epuration of EVLP with a dialyzer, while correcting features of the perfusate composition and maintaining the respiratory function, promotes inflammatory responses in the tissue. This finding suggests that modifying the metabolite composition of the perfusate by dialysis during EVLP can have detrimental effects on the tissue response and that this strategy should not be transferred as such to the clinic.

Differential early response of monocyte/macrophage subsets to intra-operative corticosteroid administration in lung transplantation.

Introduction: Lung transplantation often results in primary and/or chronic dysfunctions that are related to early perioperative innate allo-responses where myeloid subsets play a major role. Corticosteroids are administered upon surgery as a standard-of-care but their action on the different myeloid cell subsets in that context is not known. Methods: To address this issue, we used a cross-circulatory platform perfusing an extracorporeal lung coupled to cell mapping in the pig model, that enabled us to study the recruited cells in the allogeneic lung over 10 hours. Results: Myeloid cells, i.e. granulocytes and monocytic cells including classical CD14pos and non-classical/intermediate CD16pos cells, were the dominantly recruited subsets, with the latter upregulating the membrane expression of MHC class II and CD80/86 molecules. Whereas corticosteroids did not reduce the different cell subset recruitment, they potently dampened the MHC class II and CD80/86 expression on monocytic cells and not on alveolar macrophages. Besides, corticosteroids induced a temporary and partial anti-inflammatory gene profile depending on cytokines and monocyte/macrophage subsets. Discussion: This work documents the baseline effects of the standard-of-care corticosteroid treatment for early innate allo-responses. These insights will enable further optimization and improvement of lung transplantation outcomes.

A cross-circulatory platform for monitoring innate allo-responses in lung grafts.

Lung transplantation is the only curative option for end-stage chronic respiratory diseases. However the survival rate is only about 50% at 5 years. Although experimental evidences have shown that innate allo-responses impact on the clinical outcome, the knowledge of the involved mechanisms involved is limited. We established a cross-circulatory platform to monitor the early recruitment and activation of immune cells in an extracorporeal donor lung by coupling blood perfusion to cell mapping with a fluorescent marker in the pig, a commonly-used species for lung transplantation. The perfusing pig cells were easily detectable in lung cell suspensions, in broncho-alveolar lavages and in different areas of lung sections, indicating infiltration of the organ. Myeloid cells (granulocytes and monocytic cells) were the dominant recruited subsets. Between 6 and 10 h of perfusion, recruited monocytic cells presented a strong upregulation of MHC class II and CD80/86 expression, whereas alveolar macrophages and donor monocytic cells showed no significant modulation of expression. This cross-circulation model allowed us to monitor the initial encounter between perfusing cells and the lung graft, in an easy, rapid, and controllable manner, to generate robust information on innate response and test targeted therapies for improvement of lung transplantation outcome.

Prognostic impact of inflammation in malignant pleural mesothelioma: A large-scale analysis of consecutive patients.

BACKGROUND: Prediction of prognosis is a key step of malignant pleural mesothelioma (MPM) management and treatment assignment. Aim of this study was to identify simple prognostic factors, focusing on inflammation-related parameters. METHODS: Baseline clinical and laboratory data were extracted from a single-center 20-year cohort of consecutive patients exhibiting a proven MPM. Inflammation-related ratios and composite scores were evaluated as prognostic indicators. RESULTS: 468 patients were identified. Mean age and BMI were 73.0 years and 25.1 kg/m2. The histologic subtype was epithelioid, sarcomatoid, or biphasic in 80.3%, 6.2%, and 13.5% of cases, respectively. Mean Neutrophil to Lymphocyte Ratio (NLR), systemic Inflammation Index (SII) and Advanced Lung cancer inflammation Index (ALI) were 5.8, 1,836.6, and 29.6. Median survival was 13.0 months. Univariate analyses revealed that age > 70 years, persistent asthenia, hemoglobin < 13 g/dL, and non-epithelioid histologic type were associated with poorer survival, as well as the following high-inflammation-related criteria: CRP > 25 mg/L, white blood cell count (WBC) > 109/dL, NLR > 5, SII > 1,270, and ALI < 18. Multivariate regression showed that age, histology, hemoglobin, and WBC were independent predictors of survival. Also, the inflammation-related factors ALI and NLR were independently associated with survival. Interestingly, hemoglobin was statistically significant predictor of survival in all multivariate models. We found higher proportion of survival > 18 months (66th percentile) in patients exhibiting SII < 2,000 and NLR < 5. CONCLUSION: The prognosis of MPM is strongly influenced by systemic inflammation and patients exhibiting higher NLR, SII and lower ALI have shorter survival, which strengthens the level of evidence about the major role played by inflammation in MPM.