In humans two lungs are formed. In some mammalians, an additional mediastinal lobe is generated, which has its own bronchus directly branching off from the trachea. Both lungs fill the thoracic cavities leaving the midportion for the mediastinal structures and the heart and the posterior midportion for the esophagus and other structures of the posterior mediastinum. The lungs are covered by the visceral pleura, whereas the thoracic wall is internally covered by the parietal pleura. Both merge at the hilum of each lung. The right lung consists of three lobes, the left of two lobes, upper, middle, and lower lobes (Fig. 2.1). The normal lung of an adult weighs 350 (right) to 250 g (left); the lung volume varies individually between 3.5 and 8 L.

Each lobe is further divided into segments (Fig. 2.2). Each upper lobe has three segments, apical, posterior, and anterior, usually numbered accordingly from 1 to 3. In the right lung, the middle lobe is divided into a lateral (4) and a medial (5) segments. On the left side, two further bronchi are found supporting the lingula with a superior (4) and inferior (5) segment. Both lower lobes are divided into a superior (6), mediobasal (7), anterobasal (8), laterobasal (9), and posterobasal (10) segment. The segments are composed of subsegments, which can, however, anatomically not be separated.

An alveolar duct together with his alveoli forms the primary lobule. This lobule is difficult to identify on histology (easier in children’s lung) and impossible on CT scan. A terminal bronchiole III splits into several alveolar ducts, is larger, and can be identified on CT scan. Histologically this secondary lobule can also be identified by its interlobular septa. Between alveoli pores do exist (pores of Kohn), which permit gas exchange between primary lobules (Fig. 2.3). Between lobules another connecting structure, the channels of Lambert, permits gas exchange.

Fissures are separating the lobes on each site. These are formed by visceral pleura. The fissures between the lower and the middle/lingula and upper lobe are usually well developed and can be followed almost to the hilum. The fissure between the upper and middle lobe clearly separates the lobes, but also other variations can occur, where the fissure is shallow and both lobes are less well separated. In addition accessory fissures can be found separating segments from their respective lobe. All these are individual variations and have no importance for disease processes.

The airways start with the trachea, which divides into the two main bronchi. The angle of the first bifurcation is 20–30° for the right and 45° for the left main bronchus. The next bifurcation is that of the lobar bronchi: the right main bronchus gives rise to the right upper lobe bronchus and builds a short intermediate bronchus, which further on divides into the mid lobe and the lower lobe bronchus. On the left side, the main bronchus splits into the upper and lower lobe bronchus, respectively. These further on give rise to 16 generations of bronchi as an average (there are some variations between the different lobes), from lobar to segmental, subsegmental, and so on. In humans the bronchial division is asymmetric: the diameter of the upper lobe bronchus is one third and the intermediate bronchus two thirds of the diameter of the main bronchus (Fig. 2.4). This asymmetric branching is found in all subsequent bronchial generations. This has important functional meaning (see below).

Finally there are four generations of bronchioli, membranous, and three generations of respiratory bronchioles. These finally give rise to alveolar ducts on which the alveoli are opened (Fig. 2.5). The alveolar periphery is built by approximately 300 millions of alveoli.

Each bronchus has its epithelial lining, which sits on a basal lamina. Next in the bronchial wall is loose connective tissue followed by a smooth muscle layer. Within the connective tissue, bronchial glands are embedded. Finally the cartilage separates the bronchial wall from adjacent structures.

The definition of bronchioles is still not solved. Most investigators agree that they should microscopically be defined by a diameter of 1 mm and less, being devoid of cartilage and having only two layers of smooth muscle cells. The size of the internal lumen can also be used macroscopically [1].

The epithelial lining changes in thickness as well as cell composition from one bronchial generation to the next one: large bronchi have usually five layers of cells, whereas in the terminal respiratory bronchiole, there is only one single layer (Fig. 2.6). In large bronchi several cell types can be discerned in an H&E-stained section: ciliated cells, goblet cells (Fig. 2.7), secretory cells, basal cells (Fig. 2.8), intermediate cells, and neuroendocrine cells (clear cells). The proportion of ciliated cells to goblet cells in humans is normally 6–8:1. Clara cells in humans are almost absent in large bronchi, while they form a major proportion in small bronchi and bronchioles (Fig. 2.9). In contrast ciliated cells are rare in small bronchi and bronchioles and finally disappear in terminal bronchioles. Neuroendocrine cells are scattered as single cells within the bronchial mucosa; few can be found in a submucosal position (Fig. 2.10). In the alveolar periphery, neuroendocrine cells usually form neuroepithelial bodies: they consist of four to six neuroendocrine cells covered by cuboidal epithelial cells (Fig. 2.11). In children these bodies are easily found, whereas in adult lung, neuroepithelial bodies are rarely discovered. This might be due to the increased size of an adult lung.

Ciliated cells are specialized cells, which cannot divide anymore (Fig. 2.7). They have to be replaced by regenerating reserve cells which differentiate into the ciliated type. The ciliated cell is attached with a small cytoplasmic “foot process” to the basal lamina and moreover held in its position by intercellular connections with the basal and the intermediate cells. On the surface numerous cilia are formed. These cilia have a double outer membrane, eight to nine outer doublets of axonemata, and one central. From the central axonema, radial spokes radiate toward the outer axonemata. On the right side of each axonema pair, there are electron dense hornlike structures, the dynein arms, which represent a topically fixed calcium-activated ATPase (Fig. 2.12) [2]. The ATPase functions as the energy provider for the axonemata movement. All cilia coordinately beat toward the upper respiratory tract and thus move the mucus up and out. In the mucus embedded are particulates, which have been inhaled. The system is usually referred as the mucociliary escalator or clearance system and represents one of the oldest clearance systems to remove harmful material from the respiratory tract.

Goblet cells are also tall columnar cells, characterized by many mucin-containing vacuoles in the apical portion of the cytoplasm (Fig. 2.7). The nucleus is small often appearing as compressed and located at the basis of the cell. As ciliated cells, goblet cells also are fixed by long slender cytoplasmic processes to the basement membrane, and adhesion molecules fix goblet cells to basal and intermediate cells. The mucus secreted by the goblet cells consists of a three-dimensional polymer network of glycoproteins. Mucin macromolecules are 70–80 % carbohydrate, predominantly glycosaminoglycans, some of them are bound to hyaluronic acid, another 20 % are proteins, and 1–2 % sulfate are bound to oligosaccharide side chains. The protein backbones of mucins are encoded by mucin genes (MUC genes), at least eight of which are expressed in the respiratory tract, although MUC5AC and MUC5B are the two principal gel-forming mucins secreted in the airway [3].

Columnar secretory cells are the third tall columnar cell species (Fig. 2.8). They are characterized by short microvilli and secretory vacuoles. They are involved into the assembly of the immunoglobulin A (IgA) with the secretory piece [4], but might also contribute to the correct consistency of the bronchial surface fluid by secreting a more watery portion to be mixed with the mucins from the goblet cells. In animal experiments, these cells have been erroneously called pneumocytes type III or tufted cells and attributed to alveoli [5]. This is incorrect, because these cells as others of the terminal bronchioli will repopulate denuded alveolar walls in many cases of regeneration, such as alveolar damage, toxic injury, etc. However, the function of these cells is still not completely understood and will need further investigation.

Intermediate cells have a polygonal shape and fill the middle portion of the bronchial epithelial layers (Fig. 2.7). The nuclei are large and have a finely distributed chromatin, and nucleoli are inconspicuous. Within this cell layers, the bronchial or central lung stem cells are expected to exist. In experimental settings, the proliferation activity within this cell layer is upregulated [6].

Basal cells: The major function of the triangular-shaped basal cells is adherence (Fig. 2.8). They sit with their long axis firmly attached to the basal membrane and with their side axis provide attachment for several other cells especially for tall columnar cells such as the ciliated and goblet cells. The basal cells are only marginally able to divide and reproduce themselves. They are not forming the stem cell pool as previously supposed (personal communication G.R. Johnson, Lovelace Respiratory Research Institute, Albuquerque, NM).

Clara cells are one of the main cell types in bronchioles in humans (in some mammals, Clara cells can be found up to the trachea). They together with pneumocytes were for a long time supposed to be the peripheral stem cells (Fig. 2.9). They are cuboidal in shape, the nucleus is positioned in the middle of the cell, and the cytoplasm forms a dome-shaped apical portion, protruding into the lumen of the bronchioles. By electron microscopy in the apical portion, vesicles can be demonstrated, which contain proteinaceous material. This adds also in the eosinophilic staining of the cells. Clara cell proteins are involved in the defense system of the bronchiole epithelial lining but also are functioning as immune modulators [7–11]. In addition Clara cell proteins are involved in growth modulation and differentiation of the developing lung [12–14]. Clara cells can divide and differentiate into cells of the bronchioles; however, they are not peripheral stem cells.

Pneumocytes are forming the epithelial layer of alveoli. The main cell population are pneumocytes type I, whereas type 2 is usually found in edges between adjacent alveoli. Type I cell is flat and thin (Fig. 2.13). By light microscopy, they can be seen when their nucleus is in the focus of the section. By electron microscopy, the cytoplasm forms a thin layer of the basal lamina. Together with endothelial cells and the basal lamina, they form the air-blood barrier. In areas where the capillary is close to the surface, the two basal laminae are fused into one, thus providing a short diffusion distance between the surface, the cytoplasm of the pneumocyte, the basal lamina, and the endothelial cell. To keep this diffusion distance short is essential for oxygenation. Pneumocytes types II are polygonal in shape and have a round large nucleus and a granular cytoplasm. On electron microscopy, these granules in part correspond to lamellar bodies, which are the storage form of surfactant and surfactant-associated proteins (Fig. 2.14). Pneumocytes type II are capable of regeneration in as far as they are formed out of the peripheral stem cell pool and further on differentiate into type I cells.