Lewisite is a strong vesicating and chemical warfare agent. Because of the rapid transdermal absorption, cutaneous exposure to lewisite can also elicit severe systemic injury. Lewisite (2.5, 5.0, and 7.5 mg/kg) was applied to the skin of Ptch1+/- /SKH-1 mice and acute lung injury (ALI) was assessed after 24 hours. Arterial blood gas measurements showed hypercapnia and hypoxemia in the lewisite-exposed group. Histological evaluation of lung tissue revealed increased levels of proinflammatory neutrophils and a dose-dependent increase in structural changes indicative of injury. Increased inflammation was also confirmed by altered expression of cytokines, including increased IL-33, and a dose-dependent elevation of CXCL1, CXCL5, and GCSF was observed in the lung tissue. In the bronchoalveolar lavage fluid of lewisite-exposed animals, there was a significant increase in HMGB1, a damage-associated molecular pattern molecule, as well as elevated CXCL1 and CXCL5, which coincided with an influx of neutrophils to the lungs. Complete blood cell analysis revealed eosinophilia and altered neutrophil-lymphocyte ratios as a consequence of lewisite exposure. Mean platelet volume and RBC distribution width, which are predictors of lung injury, were also increased in the lewisite group. These data demonstrate that cutaneous lewisite exposure causes ALI and may contribute to mortality in exposed populations.

Cutaneous lewisite exposure causes acute lung injury

Neutrophilic dermatoses (ND) are a polymorphous group of noncontagious dermatological disorders that share the common histological feature of a sterile cutaneous infiltration of mature neutrophils. Clinical manifestations can vary from nodules, pustules, and bulla to erosions and ulcerations. The etiopathogenesis of neutrophilic dermatoses has continuously evolved. Accumulating genetic, clinical, and histological evidence point to NDs being classified in the spectrum of autoinflammatory conditions. However, unlike the monogenic autoinflammatory syndromes where a clear multiple change in the inflammasome structure/function is demonstrated, NDs display several proinflammatory abnormalities, mainly driven by IL-1, IL-17, and tumor necrosis factor-alpha (TNF-a). Additionally, because of the frequent association with extracutaneous manifestations where neutrophils seem to play a crucial role, it was plausible also to consider NDs as a cutaneous presentation of a systemic neutrophilic condition. Neutrophilic dermatoses are more frequently recognized in association with respiratory disorders than by chance alone. The combination of the two, particularly in the context of their overlapping immune responses mediated primarily by neutrophils, raises the likelihood of a common neutrophilic systemic disease or an aberrant innate immunity disorder. Associated respiratory conditions can serve as a trigger or may develop or be exacerbated secondary to the uncontrolled skin disorder. Physicians should be aware of the possible pulmonary comorbidities and apply this knowledge in the three steps of patients' management, work-up, diagnosis, and treatment. In this review, we attempt to unravel the pathophysiological mechanisms of this association and also present some evidence for the role of targeted therapy in the treatment of both conditions.

/pdf/neutrophilic-dermatoses-and-their-implication-in-3xytuhk9ts.pdf

Neutrophilic Dermatoses and Their Implication in Pathophysiology of Asthma and Other Respiratory Comorbidities: A Narrative Review

Flora and mucosal immunity are considered to be the barrier, which is associated with multiple respiratory diseases, including recurrent respiratory tract infection (RRTI). Fei-Xi-Tiao-Zhi-Fang (FTF) is a traditional Chinese herbal formula used in the treatment of RRTI. However, the mechanism is little known. This study aims to identify the function of FTF in flora and mucosal immune secretory immunoglobulin A (sIgA) in the model of RRTI rats. The samples of intestine and lung were collected to detect sIgA, short chain fatty acids (SCFAS), and flora with enzyme-linked immunosorbent assay (ELISA), gas chromatography, and 16S rDNA sequencing. The body weight and viscera index were increased dynamically in RRTI rats after the administration of FTF. Furthermore, the types and proportions of aboriginal flora were significantly changed in the model group, whereas the altered flora was rescued in the FTF administration group. Desulfovibrio increased in the intestinal microflora and Ralstonia and Blautia decreased in the pulmonary microflora at the genus level, similar to that in the normal group. In addition, the expressions of sIgA in pulmonary and intestinal tissues were significantly upregulated and the level of SCFAS was increased in FTF group compared to the RRTI model group. Our study suggests that FTF can alleviate the symptoms of RRTI by increasing sIgA and SCFAS, recovering flora, and improving the immunity.

/pdf/regulation-effect-of-a-chinese-herbal-formula-on-flora-and-28fxxc0o3x.pdf

Regulation Effect of a Chinese Herbal Formula on Flora and Mucosal Immune Secretory Immunoglobulin A in Rats

Increasing attention has been attracted to host microbiota, due to their vital impact on host health. Little is known about the microbiota of the Chinese giant salamander (Andrias davidianus), in spite of the high economic and scientific value of this endangered species. This study was designed to characterise and compare the gut and lung prokaryotic communities of the Chinese giant salamander by high-throughput sequencing. Our study showed that the giant salamander had a lung prokaryotic community that clustered separately from its intestinal microbiota. Statistical analysis (LEfSe) revealed that the bacterial populations were dominated by Geobacter, Sulfurimonas, and Dechloromonas from Proteobacteria phylum, and Corynebacterium from Actinobacteria phylum in the lung, while Parabacteroides, Bacteroides, and PW3 from Bacteroidetes phylum, and Oscillospira from Firmicutes phylum were predominant in the intestine. A particularly innovative finding was the fairly high abundance of Archaea, especially methanogenic Euryarchaeota. The gut dominant Archaea were Methanocorpusculum and Thermoplasmata vadinCA11, while Methanosaeta and Methanoculleus were the main Archaea in the lung. PICRUSt analysis revealed differentiated functional profiles between the intestinal miacrobiota and the lung microbiota. Specially, some microbial metabolic functions were significantly more active in the intestinal microbiota, while the functional genes involved in infectious diseases were much richer in the lung microbiota. This study characterized the prokaryotic microbial community profiles in the gut and lung of the Chinese giant salamander, providing foundational support for future study seeking to understand microbiota of the giant salamander and the role of its microbiota on infectious diseases.

High-throughput sequencing reveals the gut and lung prokaryotic community profiles of the Chinese giant salamander (Andrias davidianus).

The increase in antibiotic resistance poses a major threat to global health. Actinomycetes, the Gram-positive bacteria of the order Actinomycetales, are fertile producers of bioactive secondary metabolites, including antibiotics. Nearly two-thirds of antibiotics that are used for the treatment of bacterial infections were originally isolated from actinomycetes strains belonging to the genus Streptomyces. This emphasizes the importance of actinomycetes in antibiotic discovery. However, the identification of a new antimicrobial compound and the exploration of its mode of action are very challenging tasks. Therefore, different approaches that enable the “detection” of an antibiotic and the characterization of the mechanisms leading to the biological activity are indispensable. Beyond bioinformatics tools facilitating the identification of biosynthetic gene clusters (BGCs), whole cell-screenings—in which cells are exposed to actinomycete-derived compounds—are a common strategy applied at the very early stage in antibiotic drug development. More recently, target-based approaches have been established. In this case, the drug candidates were tested for interactions with usually validated targets. This review focuses on the bioactivity-based screening methods and provides the readers with an overview on the most relevant assays for the identification of antibiotic activity and investigation of mechanisms of action. Moreover, the article includes examples of the successful application of these methods and suggestions for improvement.

/pdf/overview-on-strategies-and-assays-for-antibiotic-discovery-3fj8by1c.pdf

Overview on Strategies and Assays for Antibiotic Discovery

Large-scale genome-mining analyses have identified an enormous number of cryptic biosynthetic gene clusters (BGCs) as a great source of novel bioactive natural products. Given the sheer number of natural product (NP) candidates, effective strategies and computational methods are keys to choosing appropriate BGCs for further NP characterization and production. This review discusses genomics-based approaches for prioritizing candidate BGCs extracted from large-scale genomic data, by highlighting studies that have successfully produced compounds with high chemical novelty, novel biosynthesis pathway, and potent bioactivities. We group these studies based on their BGC-prioritization logics: detecting presence of resistance genes, use of phylogenomics analysis as a guide, and targeting for specific chemical structures. We also briefly comment on the different bioinformatics tools used in the field and examine practical considerations when employing a large-scale genome mining study.

/pdf/targeted-large-scale-genome-mining-and-candidate-1uvzj0uj.pdf

Targeted Large-Scale Genome Mining and Candidate Prioritization for Natural Product Discovery

Research on allergy has recently uncovered an apparent co-occurrence of allergies in skin and the lungs, a phenomenon that has been coined “atopic march”. A positive correlation has been found between gut microbiota at birth and the development of asthma and skin eczema later in life. Chinese medicine has long described a functional relationship between the large intestine and the lungs, and between the lungs and skin. In this short article, we examined the evidence in support of these inter-organ physiological/pathological relationships. In addition to the clinical observation of the relationship between the composition of gut microbiota at birth and the development of asthma later in childhood, gut microorganisms have also been shown to exert a protective effect on bacteria-induced pneumonia in experimental animals. Genetic predisposition was also found to play an important role in the co-existence of certain diseases of lung and skin. Despite the fact that the mechanism(s) underlying the connection of immune systems between two organs (such as the large intestine and the lungs) is still not clearly understood, it is the first time to correlate the relationship among gut, lung and skin based on recent clinical studies in relation to the Zang-Fu Theory in Chinese medicine. Future investigation of the gut-lung and lung-skin axes in terms of physiological/pathological relationships may help to provide a greater understanding of the pathogenesis of allergies, possibly establishing relevance to the Zang-Fu Theory in Chinese medicine.

/pdf/inter-organ-relationships-among-gut-lung-and-skin-beyond-the-4r40j6xv5y.pdf

Hiu Yu Cherie Leung

Papers

Targeted Large-Scale Genome Mining and Candidate Prioritization for Natural Product Discovery

Inter-Organ Relationships among Gut, Lung and Skin beyond the Pathogenesis of Allergies: Relevance to the Zang-Fu Theory in Chinese Medicine