Resolution of Inflammation in Asthma

Inflammation and resolution are dynamic processes comprised of inflammatory activation and neutrophil influx, followed by mediator catabolism and efferocytosis. These critical pathways ensure a return to homeostasis and promote repair. Over the past decade research has shown that diverse mediators play a role in the active process of resolution. Specialized pro-resolving mediators (SPMs), biosynthesized from fatty acids, are released during inflammation to facilitate resolution and are deficient in a variety of lung disorders. Failed resolution results in remodeling and cellular deposition through pro-fibrotic myofibroblast expansion that irreversibly narrows the airways and worsens lung function. Recent studies indicate environmental exposures may perturb and deregulate critical resolution pathways.

Environmental xenobiotics induce lung inflammation and generate reactive metabolites that promote oxidative stress, injuring the respiratory mucosa and impairing gas-exchange. This warrants recognition of xenobiotic associated molecular patterns (XAMPs) as new signals in the field of inflammation biology, as many environmental chemicals generate free radicals capable of initiating the inflammatory response. Recent studies suggest that unresolved, persistent inflammation impacts both resolution pathways and endogenous regulatory mediators, compromising lung function, which over time can progress to chronic lung disease. Chronic ozone (O₃) exposure overwhelms successful resolution, and in susceptible individuals promotes asthma onset. The industrial contaminant cadmium (Cd) bioaccumulates in the lung to impair resolution, and recurrent inflammation can result in chronic obstructive pulmonary disease (COPD). Persistent particulate matter (PM) exposure increases systemic cardiopulmonary inflammation, which reduces lung function and can exacerbate asthma, COPD, and idiopathic pulmonary fibrosis (IPF). While recurrent inflammation underlies environmentally induced pulmonary morbidity and may drive the disease process, our understanding of inflammation resolution in this context is limited. This review aims to explore inflammation resolution biology and its role in chronic environmental lung disease(s).

Current literature implicates arachidonic acid-derived leukotrienes and prostaglandins in the pathogenesis of chronic rhinosinusitis. However, other omega-3 and omega-6 derived lipid mediators, such as specialized pro-resolving mediators (SPMs), may also be important in chronic inflammatory disorders of the upper airway. We hypothesize that SPMs differ among CRS subtypes compared to controls and in relation to sinonasal microbiota. Ethmoid sinus tissue and middle meatal swabs were collected from a convenience sample of 66 subjects, including non-CRS controls, CRS with polyps (CRSwNP), and CRS without polyps (CRSsNP). Lipid mediator pathways were analyzed by liquid chromatography/tandem mass spectrometry. Bacterial taxa were profiled in parallel by 16S rRNA gene sequencing. Resolvin D2 was elevated in both CRSwNP (p = 0.00076) and CRSsNP (p = 0.030) compared with non-CRS controls. Lipoxin A₄ was significantly increased in CRSwNP compared with CRSsNP (p = 0.000033) and controls (p = 0.044). Cigarette smoking was associated with significantly lower concentrations of several 15-lipoxygenase metabolites including resolvin D1 (p = 0.0091) and resolvin D2 (p = 0.0097), compared with never-smokers. Several of the lipid compounds also correlated with components of the sinonasal mucosal microbiota, including bacterial pathogens such as Pseudomonas aeruginosa. These data suggest that dysfunctional lipid mediator pathways in CRS extend beyond the traditional descriptions of leukotrienes and prostaglandins and include SPMs. Furthermore, dysregulated SPM signaling may contribute to persistent inflammation and bacterial colonization in CRS.

The average respiration rate for an adult is 12–20 breaths per minute, which constantly exposes the lungs to allergens and harmful particles. As a result, respiratory diseases, which includes asthma, chronic obstructive pulmonary disease (COPD) and acute lower respiratory tract infections (LTRI), are a major cause of death worldwide. Although asthma, COPD and LTRI are distinctly different diseases with separate mechanisms of disease progression, they do share a common feature – airway inflammation with intense recruitment and activation of granulocytes and mast cells. Neutrophils, eosinophils, basophils, and mast cells are crucial players in host defense against pathogens and maintenance of lung homeostasis. Upon contact with harmful particles, part of the pulmonary defense mechanism is to recruit these cells into the airways. Despite their protective nature, overactivation or accumulation of granulocytes and mast cells in the lungs results in unwanted chronic airway inflammation and damage. As such, understanding the bright and the dark side of these leukocytes in lung physiology paves the way for the development of therapies targeting this important mechanism of disease. Here we discuss the role of granulocytes in respiratory diseases and summarize therapeutic strategies focused on granulocyte recruitment and activation in the lungs.

The adaptogens modulate expression of genes playing key roles in development of aging-related disorders, which are considered as low-grade systemic inflammatory conditions characterized by an imbalance between pro-and anti-inflammatory eicosanoids.

We compared the effects of anti-inflammatory and adaptogenic plant extracts on the expression of genes involved in biosynthesis of eicosanoids with the purpose to find those plants, which selectively upregulated the expression of anti-inflammatory lipoxins signaling pathways and inhibited pro-inflammatory signaling pathways associated with biosynthesis of leukotrienes, prostaglandins and thromboxanes.

We conducted transcriptome-wide RNA sequencing to profile gene expression alterations in T98G neuroglia cells upon treatment of plant extract and analyzed the relevance of deregulated genes to eicosanoids signaling pathways using in silico models.

For the first time, we demonstrated that Rhodiola rosea, Withania somnifera and Eleutherococcus senticosus downregulate the expression of key genes (ALOX5AP, DPEP2, LTC4S) involved biosynthesis of leukotrienes A, B, C, D and E, resulting in inhibition of leukotriene signaling pathway suggesting their potential benefits in Alzheimer disease. The common feature for all tested anti-inflammatory plants extracts was related to downregulation of ALOX12, which was also associated with neuroprotective action of these medicinal plants as well as their potential benefits in neurodegenerative diseases. None of tested anti-inflammatory and adaptogenic plants selectively activated the ALOX15-mediated signaling pathway, which is associated with generation anti-inflammatory lipoxins. Almost all tested plants upregulated the expression of the prostaglandin E receptor 3 gene (PTGER3) suggesting their potential benefits in the treatment of cancer.

Every single plant tested in this study revealed a specific “signature” on eicosanoid signaling-related gene expression, regardless of their common features as anti-inflammatory or adaptogenic activity. Further studies of the combination of Rhodiola with Withania (Adaptra) for the treatment of Alzheimer disease are required.

Aerobic life is based on numerous metabolic oxidation reactions as well as biosynthesis of oxygenated signaling compounds. Among the latter are the myriads of oxygenated lipids including a well-studied group of polyunsaturated fatty acids (PUFA) - octadecanoids, eicosanoids, and docosanoids. During the last two decades, remarkable progress in liquid-chromatography-mass spectrometry has led to significant progress in the characterization of oxygenated PUFA-containing phospholipids, thus designating the emergence of a new field of lipidomics, redox lipidomics. Although non-enzymatic free radical reactions of lipid peroxidation have been mostly associated with the aberrant metabolism typical of acute injury or chronic degenerative processes, newly accumulated evidence suggests that enzymatically catalyzed (phospho)lipid oxygenation reactions are essential mechanisms of many physiological pathways. In this review, we discuss a variety of contemporary protocols applicable for identification and quantitative characterization of different classes of peroxidized (phospho)lipids. We describe applications of different types of LCMS for analysis of peroxidized (phospho)lipids, particularly cardiolipins and phosphatidylethanolalmines, in two important types of programmed cell death - apoptosis and ferroptosis. We discuss the role of peroxidized phosphatidylserines in phagocytotic signaling. We exemplify the participation of peroxidized neutral lipids, particularly tri-acylglycerides, in immuno-suppressive signaling in cancer. We also consider new approaches to exploring the spatial distribution of phospholipids in the context of their oxidizability by MS imaging, including the latest achievements in high resolution imaging techniques. We present innovative approaches to the interpretation of LC–MS data, including audio-representation analysis. Overall, we emphasize the role of redox lipidomics as a communication language, unprecedented in diversity and richness, through the analysis of peroxidized (phospho)lipids.

Arachidonate 5-lipoxygenase (ALOX5) is an essential enzyme for the biosynthesis of leukotrienes, which are pro-inflammatory and anti-inflammatory mediators. In this study, the ALOX5 paralog of the big-belly seahorse (Hippocampus abdominalis; HaALOX5) was identified from our transcriptome database, and then molecularly and functionally characterized to determine its oxygenation capability and expression under pathogenic stress. The coding sequence of HaALOX5 consisted of 2025 bp and encoded a protein of 674 amino acids in length. Sequence and phylogenetic tree analysis of HaALOX5 revealed a close relationship with its corresponding teleost HaALOX5 counterparts. Structure prediction detected an N-terminal regulatory C2-like domain and a C-terminal catalytic domain, which are the two main functional domains in ALOX5 enzymes. Quantitative PCR showed that HaALOX5 was expressed in all the analyzed tissues at different magnitudes. The highest expression was detected in the intestine and stomach. In blood cells, the liver and the intestine, HaALOX5 transcripts were significantly elevated at many post injection time points, when immune challenged with lipopolysaccharide, polyinosinic:polycytidylic acid, and Streptococcus iniae, indicating its contribution to post immune defense mechanisms in the seahorse.