Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development

Abstract

Successes in the field of respiratory medicines are largely limited to three main target classes: β2 -adrenergic receptor agonists, muscarinic antagonists and corticosteroids. A significant factor in attrition during the development of respiratory medicines is the induction of foamy macrophage responses, particularly, in rats. The term foamy macrophage describes a vacuolated cytoplasmic appearance, seen by light microscopy, which is ultrastructurally characterized by the presence of lysosomal lamellar bodies, neutral lipid droplets or drug particles. We propose a simple classification, based light-heartedly on the theme 'the good, the bad and the ugly', which allows important distinctions to be made between phenotypes, aetiologies and adversity. Foamy macrophages induced in rat lungs by exposure to inhaled β2 -agonists, antimuscarinics and corticosteroids are simple aggregates of uniform cells without other associated pathologies. In contrast, macrophage reactions induced by some other inhaled drug classes are more complex, associated with neutrophilic or lymphocytic infiltrations with/without damage to the adjacent alveolar walls. Foamy macrophage responses induced by inhaled drugs may be ascribed to either phagocytosis of poorly soluble drug particles, or to pharmacology. Both corticosteroids and β2 -agonists increase surfactant synthesis whereas muscarinic antagonists may decrease surfactant breakdown, due to inhibition of phospholipase C, both of which lead to phagocytosis of excess surfactant. Simple foamy macrophage responses are considered non-adverse, whereas ones that are more complex are designated as adverse. The development of foamy macrophage responses has led to confusion in interpretation and we hope this review helps clarify what is in fact a relatively simple, predictable, easily interpretable, commonly induced change.

Insights on animal models to investigate inhalation therapy: Relevance for biotherapeutics

“…Related to the phenomenon of lung overload in rats, is the effect of poorly soluble drug particles on alveolar macrophage populations. It is has been reported that focal macrophage accumulations often with a "foamy" appearance are a frequent observation in non-clinical toxicology studies of dry powder formulations not only in rats, but non-rodent species as well (Forbes et al, 2014;Lewis et al, 2014). Above certain particle burdens, a progressive neutrophilic inflammation will develop with infiltration of inflammatory cells and elevated pro-inflammatory cytokine production.…”

Morphometric Characterization of Rat and Human Alveolar Macrophage Cell Models and their Response to Amiodarone using High Content Image Analysis

“…Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are an area of unmet clinical need despite considerable investment in developing new therapeutics in this area [ 1 , 2 ]. New inhaled medicines require extensive non-clinical safety assessment before progressing to the clinic for evaluation of safety and efficacy in humans [ 1 – 6 ].…”

“…New inhaled medicines require extensive non-clinical safety assessment before progressing to the clinic for evaluation of safety and efficacy in humans [ 1 – 6 ]. It is not uncommon for alveolar macrophage responses to be observed in histological lung slices of animals during non-clinical inhalation toxicology studies: these are typically characterised by a highly vacuolated appearance and larger cell size [ 2 , 3 ]. These cell responses may be unaccompanied by other changes or may be associated with other immune cell infiltration or remodelling of lung tissue [ 2 , 3 ].…”

“…It is not uncommon for alveolar macrophage responses to be observed in histological lung slices of animals during non-clinical inhalation toxicology studies: these are typically characterised by a highly vacuolated appearance and larger cell size [ 2 , 3 ]. These cell responses may be unaccompanied by other changes or may be associated with other immune cell infiltration or remodelling of lung tissue [ 2 , 3 ]. As the mechanism for induction of this alveolar macrophage phenotype and its relation to lung pathophysiology are not well understood, safe exposure levels are set without knowing whether these observations are truly an adverse response or an adaptation to high doses [ 2 – 4 ].…”

microRNA-802/Rnd3 pathway imposes on carcinogenesis and metastasis of fine particulate matter exposure

“…Enlarged and foamy macrophages, associated with pronounced lymphocyte infiltration, were observed in mice lungs treated with PM 2.5 for 7 days (Figure 5C). This type of macrophage reaction was clearly adverse and had the potential to induce long-term, irreversible alterations to the pulmonary structure [25]. Massive lymphocytes surrounding the black pigment deposited in lung tissue and thickened alveolar walls were demonstrated in mice lungs after 28 days of treatment (Figure 5E, 5F).…”