at least the first 2 postnatal years. Growth of the lung continues through late adolescence (Gauderman et al. 2004). There are > 40 morphologically differenti- ated cell types in the mature lung (Warburton et al. 1998). The development of each of these differentiated cell types is influenced by the spatial and temporal distribution of a variety of signaling molecules and their receptors, which regulate normal morphologic structure and function. Branching morphogenesis. Repeatedly branched structures develop when there is a need to maximize the contact between a struc- ture and the surrounding environment. This organizational strategy packs a large area of contact into a small space (Davies 2006) and is a highly conserved process for organ growth in many structures, including the lung, kidney, salivary glands, prostate, and breast. Branching morphogenesis is a recurring, iterative pattern- ing event of bud growth, bud elongation, and subdivision of terminal units (Cardoso 2004). In the lung, branching is used to generate the bronchial tree, including secretory glands, blood vessels, and interalveolar septa. Mesenchyme develops from the mesoderm and gives rise to the lung’s connective tissue, endothelial cell precursors, smooth muscle that surrounds the airways and blood vessels, the lymphatic system, and the pleura. The lung develops in proximal-to-distal fashion but also in a specified right/left asymmetrical manner. These events develop in a cascade, each building on earlier activity and reiter- ated over several generations of branching to form the respiratory tree. Although many details of the regulation of these events are still unknown, numerous animal studies have illu- minated many of the signaling pathways and transcription factors that direct lung develop- ment. Physical factors such as stretch and fluid volume also influence lung development. Perhaps more important from a toxico- logic perspective, reciprocal exchange of signaling factors between epithelial and mes- enchymal cells is essential to normal develop- ment (reviewed by Cardoso and Lu 2006). For example, members of the fibroblast growth factor (FGF) family, soluble factors produced in the mesenchymal cells that signal tyrosine kinase receptors (Fgfr1–4) in the epithelial cells, are essential for bud initiation. Studies in organ culture show that the epithelium will migrate and proliferate toward Fgf10 (Park et al. 1998). Correct development of lung branching requires temporal and spatial con- trol over Fgf10 levels (Bellusci et al. 1997; Mariani 2007). In rodents, deletion of Fgf10 or lack of retinoic acid (RA), a crucial cofactor for FGFs, results in lung agenesis (Cardoso and Lu 2006; Desai et al. 2004; Sekine et al. 1999). Inhibitory control over Fgf10 involves sprouty (Spry2) and sonic hedgehog (Shh), Impact of environmental chemicals on lung development which are highly diffusible factors secreted by the epithelium of the developing lung bud (Mason et al. 2006; Warburton et al. 2005). The Fgf10 in the distal mesenchyme diffuses into the epithelial bud and binds to the recep- tor, Fgfr2b, to induce budding and initiate branching (Bellusci et al. 1997). Fgfr2 activity induces Spry2, which inhibits FGF signal- ing and inhibits bud growth (Mailleux et al. 2001). Shh is highly expressed in the bud’s distal epithelium (Cardoso 2004). Shh from the bud is believed to progressively down- regulate FGF activity as the bud grows toward the Fgf10-expressing mesenchyme (Lebeche et al. 1999). In mice, overexpression of Spry2 or inhibition of Shh results in impairment of branching (Bellusci et al. 1997; Cardoso 2004; Lebeche et al. 1999; Mailleux et al. 2001). Vascular endothelial growth factors (VEGF), necessary for development of the lung vasculature, are expressed in both branching tubular airways and vascular mesen- chymal cells. The coordinated development of the epithelial and endothelial compartments depends on a VEGF gradient being present from its production at the tips of growing airway tubules (Voelkel et al. 2006). In a number of murine models, overexpression of VEGF results in dysmorphogenesis, and underexpression of VEGF or neutralization of VEGF results in poor septal formation and emphysematous changes (Gerber et al. 1999; Voelkel et al. 2006). These are only examples of the many signaling pathways that must be expressed in a precise temporal and spatial pattern for normal lung growth and develop- ment (Maeda et al. 2007). The trachea develops from an outpouching of the foregut and requires formation of a separation between the two tissues. Mice deficient in Shh or RA or that lack Nkx2.1, the gene for a transcription factor active in early lung development [also called thy- roid transcription factor 1 (Ttf1)], develop an incomplete separation of the foregut and trachea known as a tracheoesophageal fistula (Litingtung et al. 1998; Minoo et al. 1999). This is a relatively common congenital anom- aly in humans and has been associated with down-regulation of the FGF pathways and aberrant Shh signaling (Crisera et al. 2000; Spilde et al. 2003). Alveolarization. As reviewed by McGowan and Snyder (2004), during the saccular phase the terminal portions of the airways give rise to alveolar ducts and sacs with thick walls of connective tissue and limited ability for gas exchange. The primary septa (the walls of the terminal sacs) have a central core of fibroblasts and connective tissue surrounded on each side by capillaries and epithelial cells. During alveolarization, ridges develop in the primary septa and become the secondary septa. In humans, a period of rapid alveolar development lasts from about 36 weeks of gestation to about 2 years of age. From sev- eral months until 3 years of age, a second phase of alveolarization occurs, characterized by microvascular remodeling, thinning and lengthening of the secondary septae, loss of mesenchymal cells, and change from a dual to a single capillary bed. From birth until maturity, there is a 20-fold increase in gas- exchange surface area (Burri 2006). Recent Figure 2. Principal stages of lung development in humans: diagrammatic representations of the timeline and developmental organization of trachea, primary bronchi, intrapulmonary bronchi, and acinus in the mammalian respiratory system. Reprinted from Pharmacology and Therapeutics, Vol 114 (Kajekar R. 2007. Environmental factors and developmental outcomes in the lung. Pharmacol Therap 114:129–145), copyright (2007), with permission from Elsevier. Environmental Health Perspectives • volume 118 | number 8 | August 2010 1157