Despite development in the understanding of the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), the underlying mechanism still needs to be elucidated. Apart from leukocytes and endothelial cells, macrophages are also essential for the process of the inflammatory response in ALI/ARDS. Notably, macrophages play a dual role of proinflammation and anti-inflammation based on the microenvironment in different pathological stages. In the acute phase of ALI/ARDS, resident alveolar macrophages, typically expressing the alternatively activated phenotype (M2), shift into the classically activated phenotype (M1) and release various potent proinflammatory mediators. In the later phase, the M1 phenotype of activated resident and recruited macrophages shifts back to the M2 phenotype for eliminating apoptotic cells and participating in fibrosis. In this review, we summarize the main subsets of macrophages and the associated signaling pathways in three different pathological phases of ALI/ARDS. According to the current literature, regulating the function of macrophages and monocytes might be a promising therapeutic strategy against ALI/ARDS.

Extracellular vesicles (EVs) are excellent potential vectors for the delivery of therapeutic drugs. However, issues with biological safety and disease targeting substantially limit their clinical application. EVs from red blood cells (RBC‐EVs) are potential drug delivery vehicles because of their unique biological safety. Here, we demonstrated that EVs, including RBC‐EVs, show natural liver accumulation. Mechanistically, the liver environment induces macrophages to phagocytize RBC‐EVs in a C1q‐dependent manner. RBC‐EVs loaded with antisense oligonucleotides of microRNA‐155 showed macrophage‐dependent protective effects against acute liver failure (ALF) in a mouse model. These RBC‐EVs were also effective in treatment of ALF. Furthermore, compared to routine doses of doxorubicin and sorafenib (SRF), RBC‐EVs loaded with doxorubicin or SRF showed enhanced therapeutic effects on a murine model of orthotopic liver cancer through a mechanism dependent on macrophages. Importantly, drug‐loaded RBC‐EVs showed no systemic toxicity at therapeutically effective doses, whereas routine doses of doxorubicin and SRF showed obvious toxicity. Thus, drug‐loaded RBC‐EVs hold high potential for clinical applications in the treatment of liver disease therapy.

Background and objectiveSepsis is a heterogeneous disease and identification of its subclasses may facilitate and optimize clinical management. This study aimed to identify subclasses of sepsis and its responses to different amounts of fluid resuscitation.MethodsThis was a retrospective study conducted in an intensive care unit at a large tertiary care hospital. The patients fulfilling the diagnostic criteria of sepsis from June 1, 2001 to October 31, 2012 were included. Clinical and laboratory variables were used to perform the latent profile analysis (LPA). A multivariable logistic regression model was used to explore the independent association of fluid input and mortality outcome.ResultsIn total, 14,993 patients were included in the study. The LPA identified four subclasses of sepsis: profile 1 was characterized by the lowest mortality rate and having the largest proportion and was considered the baseline type; profile 2 was characterized by respiratory dysfunction; profile 3 was characterized by multiple organ dysfunction (kidney, coagulation, liver, and shock), and profile 4 was characterized by neurological dysfunction. Profile 3 showed the highest mortality rate (45.4%), followed by profile 4 (27.4%), 2 (18.2%), and 1 (16.9%). Overall, the amount of fluid needed for resuscitation was the largest on day 1 (median 5115 mL, interquartile range (IQR) 2662 to 8800 mL) and decreased rapidly on day 2 (median 2140 mL, IQR 900 to 3872 mL). Higher cumulative fluid input in the first 48 h was associated with reduced risk of hospital mortality for profile 3 (odds ratio (OR) 0.89, 95% CI 0.83 to 0.95 for each 1000 mL increase in fluid input) and with increased risk of death for profile 4 (OR 1.20, 95% CI 1.11 to 1.30).ConclusionThe study identified four subphenotypes of sepsis, which showed different mortality outcomes and responses to fluid resuscitation. Prospective trials are needed to validate our findings.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2279-3) contains supplementary material, which is available to authorized users.

Asthma is a chronic inflammatory disease, with hyper-responsive bronchoconstriction and airway remodelling, leading to extensive airway narrowing. The regulation of airway responsiveness and inflammation by endogenous hydrogen sulfide (H 2 S) during the pathogenic development of asthma has been suggested. Hydrogen sulfide can be produced in the lung and airway tissues via the actions of two H 2 S-generating enzymes, cystathionine β-synthase (CBS) and/or cystathionine γ-lyase (CSE). The abnormal metabolism and function of H 2 S have been reported in experimental animals with asthma, especially ovalbumin-induced rat or mouse models. In patients with asthma, serum H 2 S levels are significantly reduced. Supplementation with exogenous H 2 S has been shown to mitigate the severity of asthma in experimental animals. It is hypothesized that decreased H 2 S production in the lung and airway tissues may be used as an early detection biomarker, and H 2 S-based therapy would represent a new treatment strategy for asthma. Major challenges for establishing the diagnostic and treatment values of H 2 S include the differential expression of CSE and CBS along the airway and their changes during asthma, the effects of H 2 S on bronchoconstriction and airway remodelling, as well as the underlying mechanisms, and the detection of the changes in H 2 S levels in airway tissues and in exhaled air.

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