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    • This study does have several limitations mainly

    2022-11-29

    This study does have several limitations, mainly related to the DMSO vehicle. While DMSO is a known anti-inflammatory mediator,5, 12 it has been shown to upregulate ALOX5, which was not seen in this study (as we are likely underpowered to detect this difference). A manifestation of this anti-inflammatory effect is the decreased PMN infiltration on histological examination after treatment with DMSO. While this does somewhat affect our results, we controlled for this by comparing the effects of MK-886 to T/HS + Vehicle alone to compare equivalent groups. These comparisons revealed significant differences between groups, showing a distinct effect due to MK-886. In addition, we only used male rats, which limits the generalizability of the results. However, this was done in light of the absence of end organ dysfunction in female rats subjected to T/HS. Finally, the choice of experimental groups and resuscitation fluids carry with them limitations. The trauma used in this model is mild compared to more severe trauma seen in human population. However, we elected to use a discrete tissue injury in place of more severe trauma that would carry with it confounding factors, either in the form of blood loss (e.g., AZ 10606120 dihydrochloride fracture or liver or splenic injury), pulmonary contusion (chest wall trauma), or head injury, which has been shown to predispose patients to lung dysfunction. Expansion of this model with additional traumatic injuries including pulmonary contusion or head injuries may provide additional avenues for research, as these are independent risk factors for lung injury, potentially through a different mechanism.13, 14, 35 We elected not to use a pure HS group as this is not seen in the trauma population of interest, but rather in conditions such as gastrointestinal hemorrhage or postpartum hemorrhage. We additionally used a high-volume normal saline resuscitation that does not reproduce modern resuscitation paradigms and may contribute to a worsened lung injury. However, this is intentional in this model, as we produce a robust lung injury, we are more easily able to detect treatment differences and limit group sizes. Post-traumatic lung injury remains a relevant clinical problem with a high burden both for the health care system and individual patients. Furthermore, the limited therapeutic options for the treatment of post-traumatic lung injury provide the essential need for further investigation of its etiology in the hopes to develop effective treatment options. As post-traumatic lung injury appears to be unique from the more general ARDS patients, targeted investigations are needed in this group. These data not only provide insight into mechanism but also highlight a possible target to ameliorate post-traumatic lung injury. Additional research is needed to establish whether MK-886 will still reduce lung damage when given following injury, as PMN priming occurs rapidly after severe injury. Currently, multiple ALOX5AP inhibitors are being studied to curtail the negative effects of leukotriene-induced chronic inflammation in asthma and chronic obstructive pulmonary disease. Whether these are beneficial in the postinjury phase is not known but may provide future avenues for research.
    Acknowledgment
    Introduction The design and construction of novel poly-heterocycles containing different privileged substructures within a same molecule, represent an important strategy in medicinal chemistry [1]. Indeed it is generally proven that the presence of two or more heterocyclic pharmacophores linked and/or fused within a same framework could contribute to provide a significant positive effect on the overall biological efficiency in the resulting poly-heterocycle [2]. Indeed and as commonly reported, coumarins represent an important class of oxygenated heterocycles extensively distributed in nature and very valued for their anti-inflammatory [3], anticancer [4], and antimicrobial activities [5]. Recently, coumarinic derivatives have also been reported to exhibit anti-tyrosinase [6], antioxidant [7], antimicrobial [8], anticoagulant [9] and anti-cholinesterase potentials [10].