Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development : Foamy Macrophage Responses in Rat Lung with Inhaled Pharmaceuticals

Recent studies have described the development of distinct functional subsets of macrophages in association with cancer, autoimmune disease, and chronic infections. Based on the ability of Th1 vs Th2 cytokines to promote opposing activities in macrophages, it has been proposed that macrophages develop into either type 1 inflammatory or type 2 anti-inflammatory subsets. As an alternative to the concept of subset development, we propose that macrophages, in response to changes in their tissue environment, can reversibly and progressively change the pattern of functions that they express. As demonstrated herein, macrophages can reversibly shift their functional phenotype through a multitude of patterns in response to changes in cytokine environment. Macrophages display distinct functional patterns after treatment with IFN-gamma, IL-12, IL-4, or IL-10 and additional functional patterns are displayed depending on whether the cytokine is present alone or with other cytokines and whether the cytokines are added before or concomitantly with the activating stimulus (LPS). Sequential treatment of macrophages with multiple cytokines results in a progression through multiple functional phenotypes. This ability to adapt to changing cytokine environments has significant in vivo relevance, as evidenced by the demonstration that macrophage functional phenotypes established in vivo in aged or tumor-bearing mice can be altered by changing their microenvironment. A concept of functional adaptivity is proposed that has important implications for therapeutic targeting of macrophages in chronic diseases that result in the dominance of particular functional phenotypes of macrophages that play a significant role in disease pathology.

Monocytes and macrophages may either promote or down-regulate inflammatory reactions depending on their state of activation. The effects of glucocorticoids (GCs), the most widely used immunosuppressive drugs, on monocytes are currently not well defined. By analyzing the GC-induced expression pattern in human monocytes by microarray technology, we identified for the first time GC-dependent regulation of 133 genes, including anti-inflammatory molecules such as adenosine A3 receptor, CD1d, and IL-1 receptor II. The results were independently confirmed by real-time polymerase chain reaction (PCR) and flow cytometry. Functional clustering of GC-regulated genes indicated induction of monocytic properties such as phagocytosis and motility as well as repression of adhesion, apoptosis, and oxidative burst. These predictions were confirmed by independent functional assays. GCs up-regulate fMLP receptors and specifically promote chemotaxis to this chemoattractant. Furthermore, GCs promote survival of an anti-inflammatory monocytic phenotype in inflammatory reactions, probably by inhibition of apoptosis because of oxidative stress. GCs limit tissue damage because of induction of antioxidative properties and high capacity for phagocytosis of proinflammatory agents. Thus, GC treatment did not cause a global suppression of monocytic effector functions but results in differentiation of a specific anti-inflammatory phenotype which seems to be actively involved in resolution of inflammatory reactions.

Pulmonary surfactant (PS) is a complicated mixture of approximately 90% lipids and 10% proteins. It plays an important role in maintaining normal respiratory mechanics by reducing alveolar surface tension to near-zero values. Supplementing exogenous surfactant to newborns suffering from respiratory distress syndrome (RDS), a leading cause of perinatal mortality, has completely altered neonatal care in industrialized countries. Surfactant therapy has also been applied to the acute respiratory distress syndrome (ARDS) but with only limited success. Biophysical studies suggest that surfactant inhibition is partially responsible for this unsatisfactory performance. This paper reviews the biophysical properties of functional and dysfunctional PS. The biophysical properties of PS are further limited to surface activity, i.e., properties related to highly dynamic and very low surface tensions. Three main perspectives are reviewed. (1) How does PS permit both rapid adsorption and the ability to reach very low surface tensions? (2) How is PS inactivated by different inhibitory substances and how can this inhibition be counteracted? A recent research focus of using water-soluble polymers as additives to enhance the surface activity of clinical PS and to overcome inhibition is extensively discussed. (3) Which in vivo, in situ, and in vitro methods are available for evaluating the surface activity of PS and what are their relative merits? A better understanding of the biophysical properties of functional and dysfunctional PS is important for the further development of surfactant therapy, especially for its potential application in ARDS.