Airway epithelial cells have the ability to produce and release antibacterial enzymes and hydrophilic-positively charged antimicrobial peptides. These substances primarily target and disrupt the cell wall components of bacteria, leading to their death. Examples of antibacterial enzymes include lysozyme, elastase, hydrolases, and secretory phospholipase A2, which target different types of pathogens. Antimicrobial peptides, on the other hand, are cationic peptides that are synthesized as propeptides and become activated by cleaving an anionic propiece. Epithelial cells and alveolar macrophages secrete peptides into the mucosal fluid, while submucosal macrophages release peptides within the local tissue.

There are three main classes of antimicrobial peptides: defensins, cathelicidins, and histatins. Defensins, categorized as α and β, have the ability to disrupt cell membranes within a matter of minutes, making them highly effective against bacteria, fungi, and viruses. β-Defensins are synthesized in alveolar type II cells and stored in lamellar bodies as a component of surfactant. α-Defensins, on the other hand, are synthesized and stored in epithelial cells, macrophages, and neutrophils. Cathelicidins are stored in secondary granules and can be activated either intracellularly by fusion of phagosomes with the granule or directly by elastase. In the lungs, cathelicidins are secreted by lung type II epithelial cells, neutrophils, and macrophages. Histatins, which are mainly found in the oral cavity, exhibit greater specificity towards pathogenic fungi. While it is uncertain whether histatins exist in the respiratory tract, carbohydrate-binding proteins (lectins) in the gut can directly kill Gram-positive bacteria by binding to their cell walls. Additionally, lactoferrins and lysozyme found in epithelial cells have been shown to have bacteriostatic and bactericidal effects. The exact mechanism of action is not fully understood, but it is speculated that they may work in synergy with iron and calcium.

While extensive research has been conducted on the gut microbiome and its role in health and disease, exploring the lung microbiome has been challenging. Initially believed to be a sterile environment, the lung presents difficulties in sampling due to invasive procedures required for sampling, the complexity and diversity of epithelial surfaces throughout the respiratory tract, and the limited availability of bacteria for sampling. Moreover, the lumen ecosystem and epithelium of the respiratory tract vary significantly along its length, from the upper airways to the alveoli, suggesting that the density and types of bacteria residing in these regions differ as well. Nonetheless, it is now evident that the lung does have a microbiome, primarily represented by three phyla: Bacteroidetes (Prevotella, Bacteroides), Firmicutes (Veillonella, Streptococcus, Staphylococcus), and Proteobacteria (Pseudomonas, Haemophilus, Moraxella, Neisseria, Acinetobacter).
Airway epithelial cells can produce and secret both antibacterial enzymes and amphipathic (hydrophilic–positively charged) antimicrobial peptides, which generally target and disrupt cell wall components of the bacteria, which leads to cell death. Lysozyme, elastase, hydrolases, and secretory phospholipase A2 are examples of antibacterial enzymes targeted at various pathogens. Antimicrobial peptides are typically cationic peptides synthesized as propeptides and activated through cleavage of an anionic propiece. Peptides secreted from epithelial cells and alveolar macrophages usually enter the mucosal fluid, whereas peptides secreted from submucosal macrophages typically stay within the local tissue.
There are three classes of antimicrobial peptides: defensins, cathelicidins, and histatins. Defensins, which are categorized as α and β can disrupt cell membranes within minutes and are very effective on bacteria, fungi, and viruses. β–Defensins are synthesized in alveolar type II cells, are stored in lamellar bodies, and are a component of surfactant. α–Defensins are synthesized and stored within epithelial cells, macrophages, and neutrophils. Cathelicidins are stored in secondary granules and activated intracellularly by fusion of the phagosomes with the granule or also directly by elastase. In the lungs, cathelicidins are secreted from lung type II epithelial cells, as well as from neutrophils and macrophages. Histatins are present mainly in the oral cavity and are more specific for pathogenic fungi. Although it is not clear whether they exist in the respiratory tract, the carbodydrate-binding proteins (lectins) in the gut can directly kill Gram-positive bacteria by binding to their cell walls. Furthermore, lactoferrins and lysozyme present in epithelial cells have been shown to have bacteriostatic and bactericidal effects; the precise mechanism by which this occurs is not clearly understood, although it is postulated that they may work synergistically with iron and calcium.
The human microbiome, especially the gut, has received a lot of attention, and exploration into the role of these commensal microorganisms in health and disease is rapidly developing. Although much is known about the gut microbiome, the lung microbiome has been difficult to explore. Once thought to be a sterile environment, the lung remains a difficult site to sample for a variety of reasons, including subject safety during sampling (invasive procedures), complexity and variety of epithelial surfaces throughout the respiratory tract, and the simple fact that far fewer bacteria are available to sample. Furthermore, the lumen ecosystem and epithelium of the respiratory tract differ considerably along the respiratory tract, from the upper airways to the alveoli; it is likely that the density and types of bacteria residing in these various regions also differ. It is clear, however, that the lung does have a microbiome, and three primary phyla appear to be represented: Bacteroidetes (Prevotella, Bacteroides), Firmicutes (Veillonella, Streptococcus, Staphylococcus), and Proteobacteria (Pseudomonas, Haemophilus, Moraxella, Neisseria, Acinetobacter).