Corticosteroid-resistant Asthma Research Articles

A Novel Catalase Nanogels for Effective Treatment of Neutrophilic Asthma

AbstractNeutrophilic asthma, as corticosteroid resistant asthma, is clinically more severe than eosinophilic asthma. Therefore, the treatment of neutrophilic asthma has been a challenging. Reactive oxygen species (ROS) play a key role in the neutrophilic asthma. However, the direct use of antioxidant enzymes, such as catalase (CAT), is challenging due to the poor stability, short plasma half‐life, and the lack of effective drug delivery systems to pulmonary systems. In this work, a novel kind of nanogels for delivering CAT (CAT‐NGs) is synthesized, incorporating CAT with an antibacterial “protective film”, as a modality for the treatment of neutrophilic asthma. Compared with free CAT, CAT‐NGs demonstrated superior enzyme activity and trypsin resistance, and exhibited outstanding anti‐inflammatory and antioxidant activities in vitro. Furthermore, CAT‐NGs showed significant inhibitory effects on nontypeable Haemophilus influenzae (NTHi), Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Additionally, nebulized inhalation of CAT‐NGs alleviated pulmonary inflammation in neutrophilic asthma mice. Mechanistically, the alleviation of neutrophilic asthma symptoms by CAT‐NGs is possibly associated with the clearance of ROS in the lung and the inhibition of the NLRP3 and NF‐κB pathways. Hence, the work have demonstrated the therapeutic potential of CAT‐NGs, offering new insights into the clinical treatment of neutrophilic asthma.

Novel Perspectives of TSLP and RXR Signaling in Corticosteroid-Resistant Asthma: Updates on TSLP Blockers.

Previous studies described that asthma patients who received corticosteroid therapy have been constrained by the corticosteroid resistance subsequently fostered to severe refractory asthma. In this review, we discussed the implications of TSLP, RXR, the role of STAT5-activating cytokines, and IL-33/NH-cell signaling pathways, and recent clinical evidence on TSLP blockers in steroid-resistant asthma. We have searched several public databases such as Pubmed, Scopus, and Relemed and obtained information pertinent to the TSLP, RXR, TSLP blockers, the STAT5-activating cytokines, and IL-33. We discussed the multiple cell signaling mechanisms underlying steroid resistance. Blocking the TSLP and other key signaling molecules like STAT5 can retrieve the sensitivity of natural helper-cells to corticosteroids. RXR derivatives treatment can modulate the activity of TSLP, which further modulates steroid resistance in severe asthmatic patients and in patients with refractory asthma. We discussed the steroid-resistance mediated by the Th2 cells and Th2-driven eosinophilia upon corticosteroid intake. Thus, this review will be beneficial for clinicians and molecular biologists to explore the inflammatory pathways associated with refractory asthma conditions and develop novel therapies against corticosteroid-resistant asthma.

Combination of Eucheuma Cottonii and Corticosteroids has a Superior Immunomodulatory Effect on Asthma

Asthma prevalence has been increasing globally which is commonly treated using corticosteroid as gold standard treatment. However, corticosteroids have adverse effects and cases of corticosteroid-resistant asthma are emerging. Eucheuma cottonii (EC) has been shown to potentially attenuate inflammatory response in type I hypersensitivity. This study aimed to investigate the effect of Eucheuma cottonii extract and methylprednisolone combination on IL-4, IL-10, and histamine levels in Ovalbumin-induced asthma BALB/c mice. Thirty female BALB/c mice were randomly assigned to 6 groups : (1) Sham; (2) Ovalbumin-induced asthma mice; (3) Ovalbumin-induced asthma mice treated with methylprednisolone (MP) 0.24 mg/day; (4) Ovalbumin-induced asthma mice treated with EC extract 300 mg/kgBW/day; (5) Ovalbumin-induced asthma mice treated with combination of both. Treatments were given respectively for 7 days. Plasma IL-4, IL-10, and histamine levels were measured using ELISA method. The combination group showed both the lowest IL-4 levels (89.30 ± 1.37 pg/ml) and the highest IL-10 levels (487.03 ± 20.57 pg/ml) compared to other asthma-like mouse groups (p = 0.001). No significant difference was observed in histamine levels among all treatments (p > 0.05). The administration of a combination of methylprednisolone and Eucheuma cottonii extract significantly affected plasma IL-4 and IL-10 levels compared to monotherapies. However, there was no significant difference in plasma histamine levels compared to monotherapies.

The effects of nebulized ketamine and intravenous magnesium sulfate on corticosteroid resistant asthma exacerbation; a randomized clinical trial

Background and aimsAsthma exacerbation is defined as an acute attack of shortness of breath with more than 25% decrease in morning peak flow compared to the baseline on 2 consecutive days, which requires immediate standard therapy. The majority of asthmatic patients are considered to be steroid-sensitive; however, corticosteroid-resistant asthma is a subset of asthma with poor response to corticosteroids and is responsible for frequent hospital admissions. In this study we aimed to compare the effects of two enhancing strategies, the nebulized ketamine and IV magnesium sulfate, in treatment of severe steroid resistant asthma.Materials and methodsThis double-blind randomized clinical trial was conducted on patients who presented to a referral clinic in Alborz, Iran. Using random allocation, patients were divided into two groups. The first group was treated with nebulized ketamine and the second group was treated with intravenous magnesium sulfate. Peak expiratory flow rates were assessed before the intervention, 30 and 60 min after the intervention and compared with the aid of SPSS software.ResultsThe Peak expiratory flow rates before the intervention, 30 min and 60 min after the intervention was statistically significantly different in both ketamine and magnesium sulfate groups. Peak expiratory flow rates change between 0 and 60 min were 29.4 and 15.2% in the ketamine and magnesium sulfate group respectively. Although the ketamine group showed much higher increase in mean PEFR compared to the MgSO4 groups, there was no statistically significant difference across both groups.ConclusionOur study concluded that combined with standard therapy, both ketamine and IV magnesium sulfate are effective agents in the improvement of PEFR in patients with acute severe asthma that failed to respond to traditional therapies. However, there were no statistically significant difference between the two groups.

Beneficial effects of infrared light-emitting diode in corticosteroid-resistant asthma.

Corticosteroid-resistant asthma (CRA) is a severe form of disease and clinically important, since patients do not respond to mainstay corticosteroid therapies. Thus, new therapies are needed. However, a big limiting factor in the understanding of CRA is the existence of different immunological and inflammatory phenotypes, a fact that makes it difficult to reproduce experimentally. Photobiomodulation (PBM) emerges as an alternative therapy based on earlier studies. This study aims to evaluate the effect of PBM using infrared light-emitting diode (ILED) on the development of corticosteroid-resistant asthma. Therefore, groups of rats were sensitized and challenged with ovalbumin plus Freund's adjuvant for the induction of CRA, and treated or not with ILED directly in the respiratory tract on the skin (wavelength 810 nm; power 100 mW; density energy 5 J/cm; total energy 15 J; time 150 s). Our experimental model was capable to induce neutrophilic asthma. Besides that, the corticosteroid treatment did not reverse the lung cell migration as well as the levels of leukotriene B4, and interleukins 17 and 6. The treatment with ILED reduced the lung cell migration; myeloperoxidase activity; mast cell degranulation; and the levels of leukotriene B4, thromboxane B2, prostaglandin E2, tumoral necrosis factor alpha, and interleukins 17 and 6. Still, ILED increased the level of interleukin 10. In conclusion, we showed promisor effects of ILED when irradiated directly in the respiratory tract as adjuvant treatment of corticosteroid-resistant asthma.

STAT3 and IL-6 Contribute to Corticosteroid Resistance in an OVA and Ozone-induced Asthma Model with Neutrophil Infiltration.

Exposure to high levels of ozone contributes to insensitivity to glucocorticoids in asthma treatment, but the underlying mechanisms are not known. We built two asthma models: a “T2-high” asthma model was established by ovalbumin (OVA) sensitization/challenge and OVA sensitization/challenge combined with ozone exposure (OVA + ozone) was used to induce airway inflammation with increased numbers of neutrophils to simulate “T2-low” asthma. The expression of T-helper (Th)1/2/17-related cytokines was measured by cytokine antibody arrays. Bronchial provocation tests were carried out to evaluate the lung resistance of mice. Hematoxylin and eosin staining, periodic acid-Schiff staining, and immunohistochemical (IHC) analyses of alpha-smooth muscle actin were undertaken to observe morphology changes in lungs. The expression of glucocorticoid receptors (GRs) and phosphorylated-GR (p-GR) was measured by western blotting. Nr3c1 mRNA was quantified by RT-qPCR. Protein expression of proinflammatory cytokines, signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3), and CXCL1 was measured through ELISAs, western blotting, or IHC analyses. Resected lung tissue from seven asthma patients and 10 healthy controls undergoing thoracotomy for pulmonary nodules was evaluated by IHC analyses and ELISAs. In both asthma models, mucus hypersecretion, as well as inflammation, hyperresponsiveness, and remodeling of the airways, was present compared with the control group, whereas the OVA + ozone group showed severe neutrophil infiltration. The expression of Th17-related cytokines (interleukin (IL)-6, IL-17A, IL-21), GR protein, and CXCL1 increased in the OVA + ozone group, whereas the expression of p-GR decreased. Dexamethasone (Dex) could not totally reverse the expression of p-GR and histone deacetylase-2 in the OVA + ozone group. STAT3 expression increased in the OVA + ozone group and could not be completely reversed by Dex, and nor could IL-6 expression. A positive correlation between IL-6 or IL-17A and STAT3 and negative correlation between SOCS3 and STAT3 were shown, suggesting that the IL-6/STAT3 pathway may be involved in OVA + ozone–induced corticosteroid-resistant airway inflammation. In clinical samples, IL-17A expression in lung tissue was positively correlated with percent STAT3-positive area and negatively correlated with SOCS3 expression. The IL-6/STAT3 pathway may contribute to corticosteroid insensitivity in OVA + ozone–induced neutrophilic airway inflammation through regulation of Th17 cells and could provide new targets for individual treatment of corticosteroid resistance in asthma.

High-dimensional profiling clusters asthma severity by lymphoid and non-lymphoid status.

SUMMARYClinical definitions of asthma fail to capture the heterogeneity of immune dysfunction in severe, treatment-refractory disease. Applying mass cytometry and machine learning to bronchoalveolar lavage (BAL) cells, we find that corticosteroid-resistant asthma patients cluster largely into two groups: one enriched in interleukin (IL)-4+ innate immune cells and another dominated by interferon (IFN)-γ+ T cells, including tissue-resident memory cells. In contrast, BAL cells of a healthier population are enriched in IL-10+ macrophages. To better understand cellular mediators of severe asthma, we developed the Immune Cell Linkage through Exploratory Matrices (ICLite) algorithm to perform deconvolution of bulk RNA sequencing of mixed-cell populations. Signatures of mitosis and IL-7 signaling in CD206−FcεRI+CD127+IL-4+ innate cells in one patient group, contrasting with adaptive immune response in T cells in the other, are preserved across technologies. Transcriptional signatures uncovered by ICLite identify T-cell-high and T-cell-poor severe asthma patients in an independent cohort, suggesting broad applicability of our findings.

Ruxolitinib inhibits poly(I:C) and type 2 cytokines-induced CCL5 production in bronchial epithelial cells: A potential therapeutic agent for severe eosinophilic asthma.

RationaleSevere eosinophilic asthma is characterized by airway eosinophilia and corticosteroid‐resistance, commonly overlapping with type 2 inflammation. It has been reported that chemokine (C‐C motif) ligand 5 (CCL5) is involved in the exacerbation of asthma by RNA virus infections. Indeed, treatment with a virus‐associated ligand and a T helper type 2 cell (Th2) cytokine can synergistically stimulate CCL5 production in bronchial epithelial cells. We aimed to evaluate the mechanisms underlying CCL5 production in this in vitro model and to assess the potential of Janus kinase 1 (JAK1) as a novel therapeutic target via the use of ruxolitinib.MethodsWe stimulated primary normal human bronchial epithelial (NHBE) cells and BEAS‐2B cells with poly(I:C) along with interleukin‐13 (IL‐13) or IL‐4, and assessed CCL5 production. We also evaluated the signals involved in virus‐ and Th2‐cytokine‐induced CCL5 production and explored a therapeutic agent that attenuates the CCL5 production.ResultsPoly(I:C) stimulated NHBE and BEAS‐2B cells to produce CCL5. Poly(I:C) and IL‐13 increased CCL5 production. Poly(I:C)‐induced CCL5 production occurred via the TLR3–IRF3 and IFNAR/JAK1–phosphoinositide 3‐kinase (PI3K) pathways, but not the IFNAR/JAK1–STATs pathway. In addition, IL‐13 did not augment poly(I:C)‐induced CCL5 production via the canonical IL‐13R/IL‐4R/JAK1–STAT6 pathway but likely via subsequent TLR3‐IRF3‐IFNAR/JAK1‐PI3K pathways. JAK1 was identified to be a potential therapeutic target for severe eosinophilic asthma. The JAK1/2 inhibitor, ruxolitinib, was demonstrated to more effectively decrease CCL5 production in BEAS‐2B cells than fluticasone propionate.ConclusionWe have demonstrated that JAK1 is a possible therapeutic target for severe corticosteroid‐resistant asthma with airway eosinophilia and persistent Th2‐type inflammation, and that ruxolitinib has potential as an alternative pharmacotherapy.

Oxidative Imbalance as a Crucial Factor in Inflammatory Lung Diseases: Could Antioxidant Treatment Constitute a New Therapeutic Strategy?

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.

Investigating MIF in Mouse Models of Severe Corticosteroid-Resistant Neutrophilic Asthma.

Experimental mouse models of asthma are widely used to investigate the underlying mechanisms of this complex and heterogeneous disease. Using mouse models of ovalbumin-induced asthma, previous investigators have established a crucial role for MIF in the development of type 2-mediated eosinophilic asthma. Surprisingly, however, the role of MIF in other phenotypes of asthma has received little attention. MIF is an important mediator of neutrophilic inflammation, and also acts to antagonize the actions of corticosteroids. Thus, MIF may play a role in the development of severe forms of asthma in which airway neutrophilia and corticosteroid insensitivity are major features. In this chapter, we provide an experimental protocol that may be used to investigate the role of MIF in a mouse model of severe corticosteroid-resistant neutrophilic asthma.

CD8+ Tc2 cells: underappreciated contributors to severe asthma.

The complexity of asthma is underscored by the number of cell types and mediators implicated in the pathogenesis of this heterogeneous syndrome. Type 2 CD4+ T-cells (Th2) and more recently, type 2 innate lymphoid cells dominate current descriptions of asthma pathogenesis. However, another important source of these type 2 cytokines, especially interleukin (IL)-5 and IL-13, are CD8+ T-cells, which are increasingly proposed to play an important role in asthma pathogenesis, because they are abundant and are comparatively insensitive to corticosteroids. Many common triggers of asthma exacerbations are mediated via corticosteroid-resistant pathways involving neutrophils and CD8+ T-cells. Extensive murine data reveal the plasticity of CD8+ T-cells and their capacity to enhance airway inflammation and airway dysfunction. In humans, Tc2 cells are predominant in fatal asthma, while in stable state, severe eosinophilic asthma is associated with greater numbers of Tc2 than Th2 cells in blood, bronchoalveolar lavage fluid and bronchial biopsies. Tc2 cells strongly express CRTH2, the receptor for prostaglandin D2, the cysteinyl leukotriene receptor 1 and the leukotriene B4 receptor. When activated, these elicit Tc2 cell chemotaxis and production of chemokines and type 2 and other cytokines, resulting directly or indirectly in eosinophil recruitment and survival. These factors position CD8+ Tc2 cells as important and underappreciated effector cells contributing to asthma pathogenesis. Here, we review recent advances and new insights in understanding the pro-asthmatic functions of CD8+ T-cells in eosinophilic asthma, especially corticosteroid-resistant asthma, and the molecular mechanisms underlying their pathologic effector function.

The Interplay between Host Immunity and Respiratory Viral Infection in Asthma Exacerbation.

Asthma is one of the most common and chronic diseases characterized by multidimensional immune responses along with poor prognosis and severity. The heterogeneous nature of asthma may be attributed to a complex interplay between risk factors (either intrinsic or extrinsic) and specific pathogens such as respiratory viruses, and even bacteria. The intrinsic risk factors are highly correlated with asthma exacerbation in host, which may be mediated via genetic polymorphisms, enhanced airway epithelial lysis, apoptosis, and exaggerated viral replication in infected cells, resulting in reduced innate immune response and concomitant reduction of interferon (types I, II, and III) synthesis. The canonical features of allergic asthma include strong Th2-related inflammation, sensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), eosinophilia, enhanced levels of Th2 cytokines, goblet cell hyperplasia, airway hyper-responsiveness, and airway remodeling. However, the NSAID-resistant non-Th2 asthma shows a characteristic neutrophilic influx, Th1/Th17 or even mixed (Th17-Th2) immune response and concurrent cytokine streams. Moreover, inhaled corticosteroid-resistant asthma may be associated with multifactorial innate and adaptive responses. In this review, we will discuss the findings of various in vivo and ex vivo models to establish the critical heterogenic asthmatic etiologies, host-pathogen relationships, humoral and cell-mediated immune responses, and subsequent mechanisms underlying asthma exacerbation triggered by respiratory viral infections.

Involvement and Possible Role of Eosinophils in Asthma Exacerbation.

Eosinophils are involved in the development of asthma exacerbation. Recent studies have suggested that sputum and blood eosinophil counts are important factors for predicting asthma exacerbation. In severe eosinophilic asthma, anti-interleukin (IL)-5 monoclonal antibody decreases blood eosinophil count and asthma exacerbation frequency. However, even in the absence of IL-5, eosinophilic airway inflammation can be sufficiently maintained by the T helper (Th) 2 network, which comprises a cascade of vascular cell adhesion molecule-1/CC chemokines/eosinophil growth factors, including granulocyte-macrophage colony-stimulating factor (GM-CSF). Periostin, an extracellular matrix protein and a biomarker of the Th2 immune response in asthma, directly activates eosinophils in vitro. A major cause of asthma exacerbation is viral infection, especially rhinovirus (RV) infection. The expression of intercellular adhesion molecule (ICAM)-1, a cellular receptor for the majority of RVs, on epithelial cells is increased after RV infection, and adhesion of eosinophils to ICAM-1 can upregulate the functions of eosinophils. The expressions of cysteinyl leukotrienes (cysLTs) and CXCL10 are upregulated in virus-induced asthma. CysLTs can directly provoke eosinophilic infiltration in vivo and activate eosinophils in vitro. Furthermore, eosinophils express the CXC chemokine receptor 3, and CXCL10 activates eosinophils in vitro. Both eosinophils and neutrophils contribute to the development of severe asthma or asthma exacerbation. IL-8, which is an important chemoattractant for neutrophils, is upregulated in some cases of severe asthma. Lipopolysaccharide (LPS), which induces IL-8 from epithelial cells, is also increased in the lower airways of corticosteroid-resistant asthma. IL-8 or LPS-stimulated neutrophils increase the transbasement membrane migration of eosinophils, even in the absence of chemoattractants for eosinophils. Therefore, eosinophils are likely to contribute to the development of asthma exacerbation through several mechanisms, including activation by Th2 cytokines, such as IL-5 or GM-CSF or by virus infection-related proteins, such as CXCL10, and interaction with other cells, such as neutrophils.

Recent Updates on Corticosteroid Resistance in Asthma

Corticosteroids are one of the most effective medications available for a wide variety of inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, autoimmune diseases, and chronic lung diseases such as asthma; however, 5–10% of asthma patients respond poorly to corticosteroids and require high doses, secondary immunosuppressants, such as calcineurin inhibitors and methotrexate, or disease-modifying biologics that can be toxic and/or expensive. Though steroid-resistant asthma affects a small percentage of patients, it consumes significant health resources and contributes to substantial morbidity and mortality. In addition, the side effects caused by excessive use of steroids dramatically impact patients’ quality of life. Recognition of patients who respond poorly to steroid therapy is important due to the persistent and considerable problems they face in managing their conditions, which bears a significant socioeconomic burden. Along with the recognition of such patients, elucidation of the molecular mechanisms of steroid resistance is equally important, so that administration of a high dosage of steroids, and the consequent adverse effects, can be avoided. This review provides an update on the mechanisms of steroid function and the possible new therapeutic modalities to treat steroid-resistant asthma.

Prevalence of Patients Eligible for Anti-IL-5 Treatment in a Cohort of Adult-Onset Asthma

Antibodies against the IL-5 pathway have been developed for the treatment of late-onset eosinophilic corticosteroid-resistant asthma. However, the prevalence of severe asthma and the proportion of patients who could benefit from such treatment among the general population of asthmatics remain unknown. To evaluate the prevalence and characteristics of patients eligible to anti-IL-5 treatment and severe asthma in an unselected cohort of adult-onset asthma. Seinäjoki Adult Asthma Study is a 12-year follow-up study of patients with new-onset adult asthma (n= 203). Prevalence was estimated based on information collected at 12-year follow-up visit. Health care use was collected from the whole 12-year follow-up period. The prevalence of anti-IL-5-treatable patients was 2%, when the following criteria were used: daily use of medium-to-high inhaled corticosteroid (ICS) dose and long-acting β2-agonist, ≥2 exacerbations/previous year and blood eosinophil count ≥300 cells/μL or fraction of exhaled nitric oxide ≥ 50 ppb. The prevalence of severe asthma, as defined according to European Respiratory Society/American Thoracic Society, was 5.9%, and only 1 patient met criteria for both groups. When compared with anti-IL-5 eligible patients, severe asthmatics were more often current smokers at diagnosis, obese, used higher ICS dose, and had higher blood neutrophils 12 years after diagnosis. Both groups differed from nonsevere asthma by a higher number of all and unplanned respiratory-related visits to health care. Severe asthmatics showed the highest number of hospitalizations. In a cohort of unselected consecutive patients with adult-onset asthma, 5.9% fulfilled criteria for severe asthma and 2% qualified for anti-IL-5 treatment. Both groups represent a high burden to health care and specifically targeted treatment could lead to lower use of health care at long term.

Potential Role of the Lung Microbiome in Shaping Asthma Phenotypes.

The introduction of 16s ribosomal RNA sequencing as a nonculture technique has led to the discovery of the presence of microbiota in the lower airways of healthy individuals. These bacterial communities may originate from the mouth and nasopharynx or from the environment by inhalation. The microbial composition of the lower airways may be modulated by dietary factors, antibiotic therapy, and microbial infections, particularly in early life. In addition, circulatory products from gut microbiota may influence the lung microbiota to maintain mucosal immunity. Recent studies have revealed that, in asthma, the lower airway microbiota show reduced diversity and community composition that is linked to severity and inflammatory phenotype. There is also a greater prevalence of proteobacteria, including Haemophilus, in symptomatic asthma. Microbial dysbiosis may contribute to both the inception and progression of asthma in infants and children, and to corticosteroid resistance in asthma. A better understanding of the regulation of the lung and gut microbiota in asthma may pave the way for targeting microbiota to prevent and treat asthma.

Combined x-ray crystallography and computational modeling approach to investigate the Hsp90 C-terminal peptide binding to FKBP51

FK506 binding protein of 51 kDa (FKBP51) is a heat shock protein 90 (Hsp90) co-chaperone involved in the regulation of steroid hormone receptors activity. It is known for its role in various regulatory pathways implicated in mood and stress-related disorders, cancer, obesity, Alzheimer’s disease and corticosteroid resistant asthma. It consists of two FKBP12 like active peptidyl prolyl isomerase (PPIase) domains (an active FK1 and inactive FK2 domain) and one tetratricopeptide repeat (TPR) domain that mediates interaction with Hsp90 via its C-terminal MEEVD peptide. Here, we report a combined x-ray crystallography and molecular dynamics study to reveal the binding mechanism of Hsp90 MEEVD peptide to the TPR domain of FKBP51. The results demonstrated that the Hsp90 C-terminal peptide binds to the TPR domain of FKBP51 with the help of di-carboxylate clamp involving Lys272, Glu273, Lys352, Asn322, and Lys329 which are conserved throughout several di-carboxylate clamp TPR proteins. Interestingly, the results from molecular dynamics study are also in agreement to the complex structure where all the contacts between these two partners were consistent throughout the simulation period. In a nutshell, our findings provide new opportunity to engage this important protein-protein interaction target by small molecules designed by structure based drug design strategy.

Airway microbiome and responses to corticosteroids in corticosteroid-resistant asthma patients treated with acid suppression medications

Airway microbiome and responses to corticosteroids in corticosteroid-resistant asthma patients treated with acid suppression medications

Bcl-2 inhibitors reduce steroid-insensitive airway inflammation

Asthmatic inflammation is dominated by accumulation of either eosinophils, neutrophils, or both in the airways. Disposal of these inflammatory cells is the key to disease control. Eosinophilic airway inflammation is responsive to corticosteroid treatment, whereas neutrophilic inflammation is resistant and increases the burden of global health care. Corticosteroid-resistant neutrophilic asthma remains mechanistically poorly understood and requires novel effective therapeutic strategies. We sought to explore the underlying mechanisms of airway inflammation persistence, as well as corticosteroid resistance, and to investigate a new strategy of effective treatment against corticosteroid-insensitive neutrophilic asthma. Mouse models of either eosinophil-dominated or neutrophil-dominated airway inflammation were used in this study to test corticosteroid sensitivity invivo and invitro. We also used vav-Bcl-2 transgenic mice to confirm the importance of granulocytes apoptosis in the clearance of airway inflammation. Finally, the Bcl-2 inhibitors ABT-737 or ABT-199 were tested for their therapeutic effects against eosinophilic or neutrophilic airway inflammation and airway hyperresponsiveness. Overexpression of Bcl-2 protein was found to be responsible for persistence of granulocytes in bronchoalveolar lavage fluid after allergic challenge. This was important because allergen-induced airway inflammation aggravated and persisted in vav-Bcl-2 transgenic mice, in which nucleated hematopoietic cells were overexpressed with Bcl-2 and resistant to apoptosis. The Bcl-2 inhibitors ABT-737 or ABT-199 play efficient roles in alleviation of either eosinophilic or corticosteroid-resistant neutrophilic airway inflammation by inducing apoptosis of immune cells, such as eosinophils, neutrophils, TH2 cells, TH17cells, and dendritic cells. Moreover, these inhibitors were found to be more efficient than steroids to induce granulocyte apoptosis exvivo from patients with severe asthma. Apoptosis of inflammatory cells is essential for clearance of allergen-induced airway inflammation. The Bcl-2 inhibitors ABT-737 or ABT-199 might be promising drugs for the treatment of airway inflammation, especially for corticosteroid-insensitive neutrophilic airway inflammation.

Bronchial asthma: a global health problem

Among the several diseases, asthma is categorized to be a chronic disorder or inflammatory ailment of the airways across the globe. Almost 18-20 million people in the United States and more than 250 million people worldwide are affected wit this syndrome. Numbers of patients are refractory to the available therapies. Newer agents are needed day by day to control symptoms and exacerbations in all patients. Over the years, there have been extensive advances in the understanding of asthma physiology at genetic level, airway biology, and immune cell signaling. Due to progression in the molecular level, diverse research groups have led to the development of number of molecules which may improve asthma care in the future. Several new classes of anti-asthma drugs—including ultra long acting β agonists, modulators of the interleukin pathways, adenosine receptor antagonist are named to be few. Some of the agents are in earlier phases of the development. Even though various groups have some preliminary efficacy data, there is insufficient confirmation to make strong recommendations about the use of these newer drugs. The mainstay of future research is on the clinical efficacy of newer agents, the effect of biological agents on severe asthma patients, and the understanding at cellular level of corticosteroid resistant asthma is needed to reduce the morbidity of asthma worldwide. The present review article is intended to give comprehensive information about the pathophysiology, pathogenesis and the medications for the management of asthma.