Bradykinin in asthma: Modulation of airway inflammation and remodelling

Bradykinin, a pro-inflammatory molecule, and its related peptides have been studied for their effects on acute reactions in upper and lower airways, where they can be synthesised and metabolized after exposure to different stimuli including allergens and viral infection. Bradykinin B1 and B2 receptors are constitutively expressed in the airways on several residential and/or immune cells. Their expression can also be induced by inflammatory mediators, usually associated with eosinophil and neutrophil recruitment, such as IL-4, IL-13, TNF-α IL-6 and IL-8, via intracellular MAPK and NF-κB signalling. In turn, the latters up-regulate both bradykinin receptors. Bradykinin activates epithelial/endothelial and immune cells, neurons and mesenchymal cells (such as fibroblasts, myofibroblasts and smooth muscle cells), which are implicated in the development of airway chronic inflammation, responsiveness and remodelling (a major feature of severe asthma). This review highlights the role of bradykinin and its receptors in respect to chronic inflammatory response involving eosinophils/neutrophils and to vascular/matrix-related airway remodelling in asthmatic airways. This scenario is especially important for understanding the mechanisms involved in the pathogenesis of eosinophilic and/or neutrophilic asthma and hence their therapeutic approach

Alpha-linolenic acid protects against cardiac injury and remodelling induced by beta-adrenergic overstimulation

α-Linolenic acid (ALA)-enriched diet prevented isoproterenol (ISO)-induced fibrosis in the ventricular myocardium.</p

Do not forget asthma comorbidities in pediatric severe asthma!

Asthma is the most common chronic respiratory disease in childhood. The long-term goals in managing asthma aim to control symptoms and prevent exacerbations, as well as to reduce side effects of therapy and mortality disease-related. Most of patients have mild to moderate asthma and respond well to standard therapies. However, a minor proportion of children with asthma has severe disease that remains uncontrolled despite optimal adherence to prescribed therapy and treatment of contributory factors, including trigger exposures and comorbidities, which can mimic or worsen asthma and contribute to exacerbations and poor quality of life. Evaluation of comorbidities is fundamental to optimize the management of the disease in a subgroup of patients with poor responder asthma. The overall aim of this article is to describe characteristics of main pediatric severe asthma comorbidities reported in literature, giving clinicians tools to recognize and manage properly these conditions

Loss of GABARAP mediates resistance to immunogenic chemotherapy in multiple myeloma

: Immunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant anti-tumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABARAP is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in high-risk MM patients. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent anti-tumor T cell response. Low GABARAP was independently associated with shorter MM patient survival and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, like bortezomib, with an autophagy inducer, like rapamycin, may improve patient outcomes in MM, where low GABARAP in the form of del(17p) is common and leads to worse outcomes

Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease.

Host immune responses at the site of Mycobacterium tuberculosis infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (TH17) responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis. Curative antimicrobial treatment reversed these observed changes. Increased IL-1β and IL-6 responses to mycobacterial stimulation were evident both in circulating monocytes and in molecular changes at the site of TST in individuals with active TB, supporting a model in which monocyte-derived IL-1β and IL-6 promote TH17 differentiation within tissues. Modulation of these cytokine pathways may provide a rational strategy for host-directed therapy in active TB

The regional distribution of in-hospital fatality among Acute Myocardial Infarction events in Italy

Aim of this paper is to investigate into the differences in the first treatment of Acute Myocardial Infarction (AMI) among Italian regional health care systems, by focusing on the regional distribution of in-hospital deaths. Starting from the theoretical care pathway (from the onset of the illness to hospitalization and recovery or possible death), the in-hospital deaths in each region are decomposed into the contributions of the attack rate, hospitalization and in-hospital fatality. The discrepancies in regional behaviour are investigated, in the aim to assess whether they can be attributed to different performances among Italian regions. The study is based on two data sources: hospital discharges, based on Diagnosis Related Groups (DRG) and provided by the Ministry of Health; death and population data by regions of residence, provided by the National Institute of Statistics