Pulmonary Host Defenses

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Chapter 22 Pulmonary Host Defenses

Theo J. Moraes, Chung-Wai Chow, Gregory P. Downey

The epithelial surface of the lung is continuously exposed to a variety of potentially pathogenic microorganisms, allergens, particulate pollutants, and other noxious agents. An intricate defense system has evolved over time to protect the lungs from these potentially harmful entities while preserving homeostasis and lung function (Figure 22-1). This system of defense mechanisms has two components: an innate (nonspecific) response and an adaptive or acquired (specific) response.

Figure 22-1 Pulmonary host defense. The pulmonary host defense system is composed of multiple components, including physical barriers such as the nose and mucous layer that lines the airways. Mechanisms also exist to remove offending microbial pathogens or noxious particles, either directly by phagocytosis or endocytosis or indirectly by mediator-regulated responses. Activation of the immune and inflammatory responses usually will facilitate resolution of the injury and clinical recovery of the patient. However, if these immune and inflammatory responses are excessive or unregulated, tissue injury and disease ensue.

The innate immune response is evolutionarily conserved to provide immediate (occurring over seconds to minutes) host defense in a broad, nonspecific manner. Only vertebrates have an additional, adaptive immune system, which is directed at specific pathogens or molecules. Although the two systems work in concert to protect the host, each has several distinctive features. With rare exceptions, the innate component of the immune system depends on proteins and signaling pathways that exist in a fully functional form, does not require priming, and is not strengthened with subsequent exposures. By contrast, the adaptive immune response requires additional time (days to weeks) (see Figures 22-2 and 22-3) to ramp up to full capacity, is specific to the pathogen (and even to specific molecular determinants of the pathogen), and has memory to provide for stronger responses with subsequent attacks (“anamnestic response”).

Figure 22-2 Timeline of pulmonary host defense mechanisms—immediate, early (seconds to hours), and late (hours to days)—that serve to protect the lung.

Figure 22-3 Interactions among the different pulmonary host defense mechanisms—immediate, early, and late. These defense mechanisms augment the immune and inflammatory responses. TLR, Toll-like receptor.

Together, these immune responses provide a formidable force to combat invading pathogenic microbes, as indicated by the rarity with which healthy humans succumb to lung infections. Specific components of the innate and adaptive host defense mechanisms are reviewed in this chapter.

Structural Defenses

With a surface area in adults of 70 m², which comes into contact with roughly 10,000 L of air a day, the lung is confronted with constant threats from microbes. In addition to inhaled pathogens, high bacterial concentrations are present in oropharyngeal secretions (10⁸/mL), and aspiration of these secretions also may pose a serious risk for invasive infection (aspiration pneumonia). Historically, the lung has been considered to be a sterile environment; recent developments in molecular analysis have provided evidence for the presence of a microbial flora of considerable diversity in the lung, which moreover is altered in disease states. Accordingly, the respiratory tract has developed a series of structural barriers that are designed both to minimize the number of pathogenic microbes entering the lungs and to hasten their clearance before an infection can be established (Table 22-1).

Table 22-1 Structural Defenses of the Airway

Structure	Functions
Nose	Filters air Warms and humidifies air Sediments particles Olfaction Sneeze reflex

Glottis

Protects from gastrointestinal and nasopharyngeal contamination

Cough reflex

Mucociliary escalator

Traps foreign particles

Facilitates physical removal of particles

Epithelium

Barrier to microbes

Mucociliary escalator

Production of antimicrobial factors

Cytokine production

Adhesion molecule expression

Particle size is an important factor determining the degree of penetration into the airways (Table 22-2). Very large particles are filtered by vibrissae (nasal hairs). Particles approximately 30 µm in diameter are removed in the nasal passages, where turbulent airflow results in prolonged air-mucosa contact, with subsequent particle impaction. Most particles between 10 and 30 µm in diameter also will be deposited on the turbinates and nasal septum, carina, or within the larger bronchi. The branching nature of the airways provides two additional mechanisms of protection: (1) the secondary, tertiary, and quaternary carinae force particles to embed in the airway mucosa, thereby preventing further penetration into the lung, and (2) reduced airflow with increased airway branching allows gravity to sediment most particles larger than 2 µm. Particles less than 0.2 to 0.5 µm across tend to stay suspended as aerosols and are exhaled. Much smaller particles (less than 0.1 µm) may be deposited as a result of brownian motion (bombardment with gas molecules).

Table 22-2 Effect of Particle Size on Penetration into Airways

Particle Size	Fate
>>>30 µm	Filtered by vibrissae
>30 µm	Nasopharyngeal impaction
10 to 30 µm	Nasopharyngeal, tracheal, and large bronchial impaction
2 to 10 µm	Sedimentation in airways
0.2 to 2 µm	Reach alveoli
0.2 to 0.5 µm	Exhaled
<0.2 µm	Exhaled or deposited (brownian motion)

Thus, only particles roughly between 2 and 0.2 µm in diameter will reach the alveoli. Unfortunately, most bacteria are from 0.5 to 2 µm in size and, when inhaled, may reach the terminal bronchioles, where they have the potential to establish an infection. Some exceptionally pathogenic bacteria require exceedingly small numbers (e.g., only 2 to 50 organisms) to establish infection.

In addition to particle size, other factors such as shape, charge, and state of hydration may influence the depth of penetration. For example, the grass heads of timothy grass, or Alternaria, can penetrate deeper into the lung than would be expected from their physical size.

Nares

The efficiency of the nose in filtering inspired air and trapping aerosolized particles has been highlighted by inhaled drug delivery studies that demonstrate better pulmonary drug deposition with mouth inhalers than with mask inhalers. Nasal congestion and increased mucus production also contribute to trapping of unwanted particles or microbes, preventing them from going further into the airways.

In addition to filtration, the nose functions to warm and humidify inspired air, thus protecting cells from physical stress and ensuring optimal performance of the mucociliary system. Olfaction also is protective, because sniffing allows potentially harmful gases to be detected before they contact the lower airways.

As noted previously, however, the upper respiratory tract may be a source of infection when aspiration of small amounts of upper airway secretions leads to compromise of the host pulmonary system. Microbial colonization is normal, and although potential pathogens can be isolated from the nasopharynx of healthy persons, under normal conditions, resident flora competitively inhibit the growth of pathogens.

Cough/Sneeze

Mechanical or chemical stimulation of receptors in the nose, larynx, or trachea or elsewhere in the respiratory tree may produce bronchoconstriction to prevent deeper penetration of irritants and also may trigger the cough or sneeze reflex to expel particles deposited in the airways (Table 22-3). The cough reflex aids mucociliary transport to remove trapped particles. Mucus usually is conveyed to the carina by the cilia and then expelled by coughing from this location. Disruption of the cough reflex (e.g., in smokers or patients with vocal cord palsy or stroke) results in a predisposition to pneumonias.

Table 22-3 Phases of Cough/Sneeze

Component	Event(s)
1. Inspiratory phase	Deep inspiration, usually 1 to 2 times tidal volume
2. Compression phase	Begins with closure of the glottis and contraction of respiratory muscles, resulting in the generation of high intrathoracic pressure (up to 100 to 200 cm H₂O in adults)
3. Expressive phase	Glottal opening, with airflow at rates as high as 25,000 cm/sec (partly helped by compression of airway cross section)
4. Relaxation phase	Relaxation of respiratory muscles with temporary bronchodilatation

Glottis

The digestive tract and the respiratory tract share both an embryologic origin and an opening to the external world (the mouth). The glottis protects the lungs from potential contamination of the airways with digestive tract material. Nevertheless, small amounts of aspiration do occur from the nasopharynx and oropharynx or esophagus in healthy people, usually without pathologic consequences. Of importance, frequent aspiration or episodes of aspiration of large amounts of material, as is seen in persons with glottic dysfunction, can lead to bacterial pneumonia and chemical pneumonitis and possibly contribute to pulmonary fibrosis.

Respiratory Epithelium

The respiratory epithelium is a highly effective barrier to microbes. Conducting airways are lined with pseudostratified columnar epithelial cells that become cuboidal as the branches extend to the alveoli. Specialized structures termed tight junctions separate the epithelial monolayer into apical (luminal) and basolateral components that form an important barrier to the passive passage of molecules and microbes from the airway lumen or alveolar space.

In addition to this important physical barrier function, epithelial cells, including ciliated cells, goblet cells, serous cells, basal cells, and Clara cells, are integral to the normal function of the mucociliary escalator, the production of a variety of antimicrobial molecules, and the initiation and regulation of inflammatory responses (see Figure 22-4).

Mucociliary Escalator

The airway epithelium is lined from the trachea to the respiratory bronchioles by the airway surface liquid (ASL), a 5- to 25-µm-thick surface film the primary function of which is to trap and facilitate the physical removal of foreign particles, as well as to provide an environment conducive to the activity of antimicrobial molecules (Table 22-4).

Table 22-4 Properties of the Mucociliary Escalator

Structure	Function(s)	Dysfunction in Disease
• Present from trachea down to level of respiratory bronchioles • 200 cilia per ciliated cell • Each cilia: 6 µm long and 0.2 µm in diameter • Thickness of layer: 5-25 µm • Inner layer: low-viscosity, periciliary solutes • Outer layer: viscous mucous blanket

• Traps foreign particles and transports them up and out of respiratory tract

Transport rate: small airways: 0.5-1 mm/min; large airways and nose: 5-20 mm/min

• Production of antimicrobial compounds

• Smokers: decreased number of ciliated cells, depressed ciliary functions

• Bronchiectasis

• Cystic fibrosis

• Primary ciliary dyskinesia

• Stents

ASL is a critical component of the mucociliary escalator and is the result of secretion by glands and serous cells and of plasma transudation (Table 22-5). The inner low-viscosity periciliary sol facilitates the coordinated beating action of the cilia that propels the outer viscous mucous blanket toward the glottis, thereby facilitating the removal of trapped pathogens or particles by expectoration or ingestion. The viscous mucus is composed of mucopolysaccharides, produced predominantly by submucous glands in the larger airways, with increasing contributions from goblet cells and Clara cells with successively larger airway generations.

Table 22-5 Properties of Airway Surface Liquid (ASL)

Composition	Function	Dysfunction in Disease
Secretions from glands and goblet cells Plasma transudation	Antimicrobial properties due to low pH and secreted antimicrobial compounds	Cystic fibrosis Asthma COPD

COPD, chronic obstructive pulmonary disease.

Dysfunction of the ASL is seen in conditions such as asthma and chronic bronchitis, in which excessive mucus is produced, resulting in airway obstruction. In cystic fibrosis, defects in ion transport are thought to reduce ASL volume, thus increasing viscosity of the mucus. This altered environment impairs mucociliary clearance and predisposes the lungs to bacterial colonization, highlighting the importance of the antimicrobial function of normal ASL.

The cilia are the second key component of the mucociliary escalator and are present from the upper airways down to the terminal bronchioles. There are approximately 200 cilia per ciliated cell. Each of these protuberances is approximately 6 µm long and 0.2 µm in diameter. The cilia are arranged longitudinally to coordinate a beating activity of 500 to 1500 beats/minute, which serves to efficiently propel the mucous layer. Abnormal ciliary function may be related to primary ciliary dyskinesia (most frequently consequent to defects in the microtubule structure of the cilia) and predisposes the lungs in affected persons to development of pneumonia and bronchiectasis. In turn, bronchiectasis, whether associated with genetic causes such as cystic fibrosis or arising as an acquired condition such as sequelae of pulmonary infections, including pulmonary tuberculosis, can lead to localized ciliary dysfunction.

Although these structural components of the respiratory system are not formally considered to be part of the immune system, together they nonetheless constitute a vital and early component of the microbial defense systems of the lung.

Specific Cell Responses

Diverse cell populations contribute to the host defense system of the lung. In addition to the cells of the respiratory epithelium, these include other structural cells of the lung, the pulmonary vascular endothelium and fibroblasts, resident leukocytes, and, at later stages of immune responses, recruited immune cells (Table 22-6), as reviewed next.

Table 22-6 Cells Mediating Pulmonary Host Defense and the Inflammatory Response

Timing	Immune Cells	Nonimmune Cells
Early phase	Monocyte-macrophages Eosinophils Mast cells Neutrophils Natural killer cells

Late phase

Epithelial Cells

The contribution of the respiratory epithelium is not limited to its roles as a structural barrier and facilitator of mucociliary clearance (Box 22-1). Respiratory epithelial cells actively participate in the regulation of inflammation and are capable of mounting an immune response by internalization of organisms and secretion of cytotoxic and antimicrobial peptides. Inhaled microbial pathogens including bacteria and viruses and other antigens can trigger activation of pathogen recognition receptors (such as Toll-like receptors [TLRs], discussed later in some detail under “Innate Immune Receptors”) expressed by epithelial cells. Epithelial cells are induced by bacterial components, such as LPS, and by cytokines such as tumor necrosis factor (TNF)-α and interleukin-1β (IL-1β) to express various gene products (by the NFκB signaling pathway, discussed later on) that modulate the inflammatory response (Figure 22-4). Such inducers include the following:

• Cytokines such as TNF-α, IL-1β, and thymic stromal lymphopoietin (TSLP)

• Chemokines that include macrophage inflammatory protein (MIP)-2, CXC chemokines, monocyte chemoattractant protein (MCP)-1, IL-7, IL-8, IL-15

• Nitric oxide (NO) and reactive nitrogen species (ONOO⁻)

• Adhesion molecules such as β-integrins and intercellular adhesion molecule-1 (ICAM-1)

• TLRs such as TLR-2 and TLR-4

• TNF-α receptors, TNFR1 and TNFR2

• Growth factor receptors such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR)

• Plasminogen activator receptors