Macrophages and dendritic cells (DCs) are derived from the bone marrow but differ in their differentiation lineage. Macrophages develop through the common myeloid-granulocyte/ macrophage progenitor linage along with other granulocytic cells (basophils, mast cells, eosinophils, neutrophils), while DCs develop through either the common lymphoid progenitor or the common myeloid progenitor lineages. Both macrophages and DCs are the first non-epithelial cells to encounter and respond to foreign substances. In the lungs, there are three major types of macrophages (alveolar, M-1 [proinflammatory], and M-2 [regulatory]) and two types of DCs (conventional and plasmacytoid).

When foreign material remains within the airspace of the lower respiratory system, specifically the alveolar ducts and alveoli, it is likely to be phagocytized by alveolar macrophages. However, if the foreign material or organism manages to penetrate and reach submucosal areas, it will come into contact with M-1 or M-2 macrophages and conventional or plasmacytoid DCs. Alveolar macrophages are predominantly found in the alveolus adjacent to the epithelium and are less common in the terminal airways and interstitial space. They freely migrate throughout the alveolar spaces, serving as a first line of defense in the terminal bronchioles and alveoli. Alveolar macrophages phagocytize foreign particles and substances, as well as surfactant and cellular debris from dead cells. The major mechanisms by which macrophages destroy particles or organisms they phagocytize include the formation of O2 radicals, enzyme activity, and the production of halogen derivatives within lysosomes.

The phagocytic activity of macrophages prevents particulates from binding to the alveolar epithelium and subsequently penetrating the interstitium. Additionally, alveolar macrophages transport engulfed particles to ciliated regions of the mucociliary transport system for elimination, establishing an important link between the alveolar spaces, the postterminal bronchiole "Achilles heel" region, and the mucociliary clearance system.

Furthermore, alveolar macrophages and M-2 macrophages present in the submucosa can suppress T cell activity through direct contact or the secretion of soluble factors such as nitric acid, prostaglandin E2, and the immunosuppressive cytokines IL-10 and TGF-β. M-1 macrophages, also located in submucosal sites, represent the classical "proinflammatory" phagocytic cell, exhibiting similar killing capabilities as alveolar macrophages. Interestingly, the proinflammatory cytokines IL-4 and IL-13, associated with Th2 responses and asthma, have been shown to promote the differentiation of M-1 macrophages into regulatory/suppressive M-2 macrophages, highlighting the plasticity of these cells. The ability of these macrophage populations to swiftly dispose of foreign material with either a proinflammatory or regulatory response greatly enhances the lung defense system and contributes uniquely to the overall mucosal defense system.
Both macrophages and DCs originate in the bone marrow but vary somewhat in their differentiation lineage: Macrophages develop through the common myeloid-granulocyte/ macrophage progenitor linage with other granulocytic cells (basophils, mast cells, eosinophils, neutrophils), and DCs develop through either the common lymphoid progenitor or the common myeloid progenitor lineages. Macrophages and DCs are the first nonepithelial cells to contact and respond to a foreign substance. In the lungs, there are three major types of macrophages (alveolar, M-1 [proinflammatory], and M-2 [regulatory]) and two types of DCs (conventional and plasmacytoid).
If the inhaled foreign material stays within the airspace in the lower respiratory system (alveolar ducts and alveoli), it will probably be phagocytized by alveolar macrophages. However, if the foreign material/organism penetrates and reaches submucosal areas, it will come into contact with M-1 or M-2 macrophages and conventional or plasmacytoid DCs. Alveolar macrophages are found mostly in the alveolus adjacent to the epithelium and less frequently in the terminal airways and interstitial space. They migrate freely throughout the alveolar spaces and serve as a first line of defense in the terminal bronchioles and alveoli. They phagocytize foreign particles and substances, as well as surfactant and cellular debris from dead cells. For a particle/organism that is phagocytized by a macrophage, the major mechanisms of destruction include formation of O2 radicals, enzyme activity, and halogen derivatives within lysosomes.
The phagocytic activity of the macrophage inhibits the binding of particulates to the alveolar epithelium and their subsequent penetration into the interstitium. The alveolar macrophage also transports engulfed particles to ciliated regions of the mucociliary transport system for elimination and thus provides an important link between the alveolar spaces, the postterminal bronchiole “Achilles heel” region, and the mucociliary clearance system.
In addition, alveolar macrophages and M-2 macrophages present in the submucosa can also suppress T cell activity by direct contact or by the secretion of soluble factors such as nitric acid, prostaglandin E2, and the immunosuppressive cytokines (IL-10 and TGF-β). M-1 macrophages are also located in submucosal sites and represent the classical “proinflammatory” phagocytic cell, with similar killing capabilities as those of alveolar macrophages. In addition, the T helper 2 (Th2) proinflammatory (and proasthma) cytokines IL-4 and IL-13 have been shown to promote the differentiation of M-1 macrophages into regulatory/suppressive M-2 macrophages, which demonstrates the plasticity of these cells. The ability of these macrophage populations to demonstrate plasticity and dispose of foreign material rapidly with either a proinflammatory or regulatory response considerably enhances the lung defense system and is a unique contributor to the overall mucosal defense system.