Respiratory infections and diseases are accompanied by or exhibit inflammation. Recent advances in nanoparticle engineering technology, together with the increased knowledge of inflammatory pathophysiology, have ignited interest in the pulmonary delivery of anti-inflammatory agents (AIAs) to achieve local treatment of pulmonary inflammatory disorders.
Areas covered: This review summarizes and discusses the investigated formulation approaches for the pulmonary delivery of AIAs, including: inhalation of actives as suspensions or dry powder formulations, with polymeric micro- and nano-delivery carriers, or within liposomes and lipid nanoparticles. Some recent approaches for targeting AIAs to the pulmonary endothelium have also been reviewed. The discussion focuses on finding out whether the investigated approaches were really able to achieve lung targeting and reduce the side effects associated with the systemic administration of AIAs. Expert opinion: The use of the inhalation route for the pulmonary delivery of AIAs is facing several challenges. Some of the investigated formulation approaches appear to be promising in overcoming these challenges. However, in order to create products that reach patients, more therapeutically oriented studies are still needed to ensure formulation stability, in-vivo sustained release behavior, pulmonary retention, and bypassing lung clearance mechanisms.

PMID: 25534260 [PubMed - as supplied by publisher]

Non-enzymatic formation of advanced glycation endproducts (AGEs) is associated with degenerative diseases. Chronic accumulation of AGEs with age in tissues especially in the extracellular matrix is well known and at least in part responsible for e.g. collagen crosslinking, tissue stiffening and thus induction of high blood pressure or diastolic heart failure. Binding of soluble AGEs to the receptor for AGEs, RAGE, induces an inflammatory response whereas the soluble form of RAGE (sRAGE) can inhibit inflammatory tissue injury like arteriosclerosis in mouse models. However, there are a number of indications that AGEs have protective effects as well. AGEs may inhibit lung tumor growth, glyoxal induced AGE modification of human heart muscle can reduce an ischemia reperfusion injury and AGEs from nutrition can reduce ROS induced cell damage. CONCLUSIONS: In summary, this indicates that protein glycation behaves like a double-edged sword. It induces tissue aging and degenerative diseases on the one hand, on the other hand, may also have protective effects, indicating a hormetic response.

PMID: 25536383 [PubMed - as supplied by publisher]

Early Events in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Smoking-induced Reprogramming of Airway Epithelial Basal Progenitor Cells.

Ann Am Thorac Soc. 2014 Dec;11 Suppl 5:S252-8

Authors: Shaykhiev R, Crystal RG

Abstract
The airway epithelium is the primary site of the earliest pathologic changes induced by smoking, contributing to the development of chronic obstructive pulmonary disease (COPD). The normal human airway epithelium is composed of several major cell types, including differentiated ciliated and secretory cells, intermediate undifferentiated cells, and basal cells (BC). BC contain the stem/progenitor cell population responsible for maintenance of the normally differentiated airway epithelium. Although inflammatory and immune processes play a significant role in the pathogenesis of COPD, the earliest lesions include hyperplasia of the BC population, suggesting that the disease may start with this cell type. Apart from BC hyperplasia, smoking induces a number of COPD-relevant airway epithelial remodeling phenotypes that are likely initiated in the BC population, including mucous cell hyperplasia, squamous cell metaplasia, epithelial-mesenchymal transition, altered ciliated and nonmucous secretory cell differentiation, and suppression of junctional barrier integrity. Significant progress has been recently made in understanding the biology of human airway BC, including gene expression features, stem/progenitor, and other functions, including interaction with other airway cell types. Accumulating evidence suggests that human airway BC function as both sensors and cellular sources of various cytokines and growth factors relevant to smoking-associated airway injury, as well as the origin of various molecular and histological phenotypes relevant to the pathogenesis of COPD. In the context of these considerations, we suggest that early BC-specific smoking-induced molecular changes are critical to the pathogenesis of COPD, and these represent a candidate target for novel therapeutic approaches to prevent COPD progression in susceptible individuals.

PMID: 25525728 [PubMed - in process]

Targeting immune pathways for therapy in asthma and chronic obstructive pulmonary disease.

Ann Am Thorac Soc. 2014 Dec;11 Suppl 5:S322-8

Authors: Brusselle G, Bracke K

Abstract
Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic inflammatory diseases of the airways, with differences in etiology, pathogenesis, immunologic mechanisms, clinical presentation, comorbidities, prognosis, and response to treatment. In mild to moderate early-onset allergic asthma, the Th2-driven eosinophilic airway inflammation and the ensuing disease can be well controlled with maintenance treatment with inhaled corticosteroids (ICS). In real-life settings, asthma control can be improved by facilitating adherence to ICS treatment and by optimizing inhaler technique. In patients with uncontrolled severe asthma, old and novel therapies targeting specific immunologic pathways should be added according to the underlying endotype/phenotype. In COPD, there is a high unmet need for safe and effective antiinflammatory treatments that not only prevent exacerbations but also have a beneficial impact on the course of the disease and improve survival. Although several new approaches aim to target the chronic neutrophilic pulmonary inflammation per se in patients with COPD, strategies that target the underlying causes of the pulmonary neutrophilia (e.g., smoking, chronic infection, and oxidative stress) might be more successful. In both chronic airway diseases (especially in more difficult, complex cases), the choice of the optimal treatment should be based not only on arbitrary clinical labels but also on the underlying immunopathology.

PMID: 25525740 [PubMed - in process]