Granulocyte-targeted therapies for airway diseases

Abstract

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 featureairway 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.

Sialic acid-binding immunoglobulin-like lectin 9 as a potential therapeutic target for chronic obstructive pulmonary disease

“…Neutrophils recruitment to the respiratory tract of COPD patients is activated owing to elevated concentrations of granule proteins including human neutrophil lipocalin and myeloperoxidase (MPO) in respiratory tract secretions. [ 16 ] Indeed, partial or global hypoxia compromises antimorphic effect and enhances the production of multiple serine proteases, such as serprocidins and matrix metalloproteinases (MMPs), resulting in further cellular and tissue injury. [ 17 , 18 ] Moreover, several neutrophil-derived inflammatory mediators including neutrophil extracellular traps (NETs), high-mobility group box 1 (HMGB1), and reactive oxygen species (ROS) have been shown to trigger small airway remodeling and alveolar destruction in patients with COPD.…”

Eosinophils and Purinergic Signaling in Health and Disease

“…Eosinophils themselves produce different cytokines including IL-1, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α, TGF-β, GM-CSF and pro-inflammatory mediators such as leukotriene C4 (LTC4), platelet-activation factor (PAF) ( 71 , 74 ), the granular cationic proteins, major basic protein (MBP) 1, MBP 2, eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPO). MBP which is present in the crystal core of the specific granules has cytotoxic effects due to interference with electrical properties and permeability of the cell membrane.…”

Novel Immunomodulatory Therapies for Respiratory Pathologies

“…Inflammation was one of the first “diseases” identified in ancient medicine and now has been considered a unifying component of several pathologies ( Tavares et al, 2020b ; Hunter, 2012 ; Parnes, 2008 ). In disease, inflammatory responses can be exaggerated, altered, or misplaced leading to tissue damage, symptoms and eventually death ( Sousa et al, 2020b ).…”

“…To keep up with the pulmonary physiological functioning, the immune system must encounter and clear infections while maintaining a high threshold of activation to prevent induction of unnecessary inflammation what can impair gas exchange, the primordial pulmonary function ( Allard et al, 2018 ; Schleimer et al, 2007 ). Dysregulation of inflammatory responses in the lungs is associated with severity of chronic diseases such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis, and acute diseases such as pneumonia ( Tavares et al, 2020b ). Recognizing the endogenous circuits of inflammation and its regulation has paved the way for the development of therapeutics for respiratory pathologies.…”