Inflammatory lung disease results in a high global burden of death and disability. There are no effective treatments for the most severe forms of many inflammatory lung diseases, such as chronic obstructive pulmonary disease, emphysema, corticosteroid‐resistant asthma, and coronavirus disease 2019; hence, new treatment options are required. Here, we review the role of oxidative imbalance in the development of difficult‐to‐treat inflammatory lung diseases. The inflammation‐induced overproduction of reactive oxygen species (ROS) means that endogenous antioxidants may not be sufficient to prevent oxidative damage, resulting in an oxidative imbalance in the lung. In turn, intracellular signaling events trigger the production of proinflammatory mediators that perpetuate and aggravate the inflammatory response and may lead to tissue damage. The production of high levels of ROS in inflammatory lung diseases can induce the phosphorylation of mitogen‐activated protein kinases, the inactivation of phosphoinositide 3‐kinase (PI3K) signaling and histone deacetylase 2, a decrease in glucocorticoid binding to its receptor, and thus resistance to glucocorticoid treatment. Hence, antioxidant treatment might be a therapeutic option for inflammatory lung diseases. Preclinical studies have shown that antioxidants (alone or combined with anti‐inflammatory drugs) are effective in the treatment of inflammatory lung diseases, although the clinical evidence of efficacy is weaker. Despite the high level of evidence for the efficacy of antioxidants in the treatment of inflammatory lung diseases, the discovery and clinical investigation of safer, more efficacious compounds are now a priority.

Glucocorticoid (GC) production is physiologically regulated through a negative feedback loop mediated by the GC, which appear disrupted in several pathological conditions. The inability to perform negative feedback of the hypothalamus‐pituitary‐adrenal (HPA) axis in several diseases is associated with an overproduction of reactive oxygen species (ROS); however, nothing is known about the effects of ROS on the functionality of the HPA axis during homeostasis. This study analyzed the putative impact of antioxidants on the HPA axis activity and GC‐mediated negative feedback upon the HPA cascade. Male Wistar rats were orally treated with N‐acetylcysteine (NAC) or vitamin E for 18 consecutive days. NAC‐treated rats were then subjected to a daily treatment with dexamethasone, which covered the last 5 days of the antioxidant therapy. We found that NAC and vitamin E induced an increase in plasma corticosterone levels. NAC intensified MC2R and StAR expressions in the adrenal and reduced GR and MR expressions in the pituitary. NAC also prevented the dexamethasone‐induced reduction in plasma corticosterone levels. Furthermore, NAC decreased HO‐1 and Nrf2 expression in the pituitary. These findings show that antioxidants induce hyperactivity of the HPA axis via upregulation of MC2R expression in the adrenal and downregulation of GR and MR in the pituitary.

Asthma represents one of the leading chronic diseases worldwide and causes a high global burden of death and disability. In asthmatic patients, the exacerbation and chronification of the inflammatory response are often related to a failure in the resolution phase of inflammation. We reviewed the role of the main arachidonic acid (AA) specialized pro-resolving mediators (SPMs) in the resolution of chronic lung inflammation of asthmatics. AA is metabolized by two classes of enzymes, cyclooxygenases (COX), which produce prostaglandins (PGs) and thromboxanes, and lypoxygenases (LOX), which form leukotrienes and lipoxins (LXs). In asthma, two primary pro-resolving derived mediators from COXs are PGE₂and the cyclopentenone prostaglandin15-Deoxy-Delta-12,14-PGJ₂(15d-PGJ₂) while from LOXs are the LXA₄and LXB₄. In different models of asthma, PGE₂, 15d-PGJ₂, and LXs reduced lung inflammation and remodeling. Furthermore, these SPMs inhibited chemotaxis and function of several inflammatory cells involved in asthma pathogenesis, such as eosinophils, and presented an antiremodeling effect in airway epithelial, smooth muscle cells and fibroblastsin vitro. In addition, PGE₂, 15d-PGJ₂, and LXs are all able to induce macrophage reprogramming to an alternative M2 pro-resolving phenotypein vitroandin vivo. Although PGE₂and LXA₄showed some beneficial effects in asthmatic patients, there are limitations to their clinical use, since PGE₂caused side effects, while LXA₄presented low stability. Therefore, despite the strong evidence that these AA-derived SPMs induce resolution of both inflammatory response and tissue remodeling in asthma, safer and more stable analogs must be developed for further clinical investigation of their application in asthma treatment.

Background: Gold nanoparticles (AuNPs) can inhibit pivotal pathological changes in experimental asthma, but their effect on steroid-insensitive asthma is unclear. The current study assessed the effectiveness of nebulized AuNPs in a murine model of glucocorticoid (GC)-resistant asthma. Methods: A/J mice were sensitized and subjected to intranasal instillations of ovalbumin (OVA) once a week for nine weeks. Two weeks after starting allergen stimulations, mice were subjected to Budesonide or AuNP nebulization 1 h before stimuli. Analyses were carried out 24 h after the last provocation. Results: We found that mice challenged with OVA had airway hyperreactivity, eosinophil, and neutrophil infiltrates in the lung, concomitantly with peribronchiolar fibrosis, mucus production, and pro-inflammatory cytokine generation compared to sham-challenged mice. These changes were inhibited in mice treated with AuNPs, but not Budesonide. In the GC-resistant asthmatic mice, oxidative stress was established, marked by a reduction in nuclear factor erythroid 2-related factor 2 (NRF2) levels and catalase activity, accompanied by elevated values of thiobarbituric acid reactive substances (TBARS), phosphoinositide 3-kinases δ (PI3Kδ) expression, as well as a reduction in the nuclear expression of histone deacetylase 2 (HDAC2) in the lung tissue, all of which sensitive to AuNPs but not Budesonide treatment. Conclusion: These findings suggest that AuNPs can improve GC-insensitive asthma by preserving HDAC2 and NRF2.

A new infectious disease, named COVID-19, caused by the coronavirus associated to severe acute respiratory syndrome (SARS-CoV-2) has become pandemic in 2020. The three most common pre-existing comorbidities associated with COVID-19-related death are elderly, diabetic, and hypertensive people. A common factor among these risk groups for the outcome of death in patients infected with SARS-CoV-2 is dysbiosis, with an increase in the proportion of bacteria with a pro-inflammatory profile. Due to this dysbiosis, elderly, diabetic, and hypertensive people present a higher propensity to mount an inflammatory environment in the gut with poor immune editing, culminating in a weakness of the intestinal permeability barrier and high bacterial product translocation to the bloodstream. This scenario culminates in a low-grade, persistent, and systemic inflammation. In this context, we propose here that high circulating levels of bacterial products, like lipopolysaccharide (LPS), can potentiate the SARS-CoV-2-induced cytokines, including IL-6, being crucial for development of the cytokine storm in the severe form of the disease. A better understanding on the possible correlation between gut dysbiosis and poor outcomes observed in elderly, diabetic, and hypertensive people can be useful for the development of new therapeutic strategies based on modulation of the gut microbiota.