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Figure 5. Model of Host-Defense Defects in the Airway of a Person with Cystic Fibrosis.As shown in Panel A, healthy airways are protected from inhaled and aspirated bacteria that enter the lung. The airway-surface liquid (left) contains endogenous antimicrobial agents that kill bacteria. Mucociliary transport (right), consisting of motile cilia and mucus produced by submucosal glands and goblet cells, sweeps bacteria out of the lung. CFTR and possibly CFTR-associated transporters provide a pathway for the exit of chloride and bicarbonate across the apical membrane of cells in the surface epithelium and in the submucosal glands. As shown in Panel B, the airway of a person with cystic fibrosis has at least two host-defense defects at the genesis of the disease. Loss of CFTR channels that conduct chloride (Cl?) and bicarbonate (HCO3 ?) onto the airway surface causes the pH of the airway-surface liquid to decrease, and the acidic airway-surface liquid inhibits antimicrobial activity. Loss of CFTR channels in submucosal glands causes mucus to develop abnormal properties so that it does not break free after emerging and remains anchored to the gland ducts. As shown in Panel C, when bacteria enter healthy airways (top), they are killed by the antimicrobial activity of airway-surface liquid, mucociliary transport sweeps them out of the lung, and other defenses, including phagocytic cells, eradicate them to maintain sterile lungs. In persons with cystic fibrosis (bottom), antimicrobial activity and mucociliary transport are less effective than in healthy persons, and other defenses may also be impaired. Eventually, the host defenses are overwhelmed, and bacteria proliferate, with inflammation, remodeling, immunity, and genetic adaptation in the bacteria influencing the species that will dominate. In addition, the resulting inflammation and airway remodeling may further enhance or impair host-defense mechanisms.

AIRWAY INFECTION PRECEDING LUNG INFLAMMATION

The chicken-and-egg conundrum about infection and inflammation has long vexed researchers and clinicians in the field During the first hours after birth, piglets with cystic fibrosis show no evidence of inflammation in their airways on histopathological analysis, measurement of cell counts and cytokines, or transcript analysis.19,26,27,38 Yet, after a pulmonary challenge withStaphylococcus aureus, they fail to eradicate bacteria as well as do the airways of controls.26Moreover, newborn piglets and neonatal ferrets with cystic fibrosis harbor more bacteria than do littermates without this disease

The species that are isolated include a wide variety of gram-positive and gram-negative organisms, including S. aureus. Although Pseudomonas aeruginosa is rare in young pigs with cystic fibrosis, it infects older pigs that have clinical disease. A similar pattern occurs in cystic fibrosis in humans; during the initial months to years of life, a wide variety of bacteria are recovered from the lungs. With time, the lungs become chronically colonized with a more restricted number of species, most notably P. aeruginosa.

These findings indicate that within hours after birth, infants with cystic fibrosis have an “equal opportunity” host-defense defect in their lungs that impairs eradication of many different types of bacteria. That abnormality can initiate a cascade of airway inflammation and airway remodeling. Later in life, the types of infection narrow to a few predominant species, probably because of an interplay between a changing host and bacterial genetic adaptations. In addition, although infection precedes inflammation, subsequent inflammatory responses, resolution of inflammation, adaptive immune responses, or all of these might be abnormal.

ACIDIC AIRWAY-SURFACE LIQUID THAT IMPAIRS BACTERIAL KILLING

Airways use multiple mechanisms to protect lungs against infection. One important defense is the complex soup of antimicrobial peptides, proteins, and lipids in airway-surface liquid. Alexander Fleming was the first to identify one of these — lysozyme — after he noticed that sneeze droplets killed bacteria on his culture dish. Since then, more factors have been identified, including lactoferrin, defensins, cathelicidins, and secretory leukocyte peptidase inhibitor. Many of these factors have individual as well as synergistic effects that rapidly kill bacteria.

In wild-type piglets, airway-surface liquid very quickly kills most S. aureus In contrast, loss of CFTR reduces rapid bacterial killing by about half. This is not due to a decreased abundance of antimicrobials in airway-surface liquid. Rather, the reduced pH of airway-surface liquid in piglets with cystic fibrosis inhibits its antimicrobial activity. Increasing the pH of airway-surface liquid by aerosolizing sodium bicarbonate onto the airways of piglets with cystic fibrosis corrects the bacterial-killing defect. Conversely, increasing the acidity of airway-surface liquid diminishes bacterial killing in wild-type piglets.

These findings directly link loss of CFTR function to a host-defense defect; without CFTR-dependent bicarbonate secretion, the pH of airway-surface liquid decreases and antibacterial activity is impaired. The reduced degree of bacterial killing may be one of the critical first steps in a downward spiral from a sterile newborn lung to one that is chronically colonized.

ADDITIONAL IMPLICATIONS AND SPECULATIONS

Discoveries from new animal models raise additional questions for future research and have implications for the care of people with cystic fibrosis, although any therapeutic implications will require assessment in humans. In addition, whether defects that are key at the origins of cystic fibrosis retain pathophysiological importance later in the disease course remains uncertain. The following paragraphs review some of the take-home points of this article.

First, the consensus based on the data reviewed here and clinical experience is that people with cystic fibrosis should be treated early. We suspect that host-defense defects begin on the day babies with cystic fibrosis are born, as they do in piglets with cystic fibrosis. That timing suggests that preventive measures should be initiated immediately. Cystic fibrosis clinics already have substantial momentum toward earlier intervention, and data provide support for that trend.

Second, the loss of CFTR delivers multiple “hits.” This loss does not completely eliminate any single defense; instead, it reduces the effectiveness of at least two defenses — mucociliary transport and antimicrobial activity44,52 — and other defenses may also be degraded6,10 (Figure 5FIGURE 5Model of Host-Defense Defects in the Airway of a Person with Cystic Fibrosis.). Compromising one host-defense mechanism places a greater burden on other defenses. If those are also impaired, problems may ensue. For example, without robust antimicrobial activity to rapidly kill bacteria, increased numbers of viable organisms might prompt submucosal-gland secretion, leading to impairment of mucociliary transport. Likewise, failure of mucus detachment might allow bacteria to grow under conditions that promote resistance to antibacterial defenses that are already diminished by cystic fibrosis.44,73 Thus, partially disrupting two or more defenses may elicit a vicious cycle of disease.

Third, cystic fibrosis initially causes an “equal opportunity” host-defense defect that may serve as a gateway for infection with typical cystic fibrosis–associated bacteria. The mix of many different bacterial species in the airways so early in the disease could elicit inflammatory, remodeling, and structural changes that become irreversible and that confer a predisposition to more intractable infections with typical cystic fibrosis pathogens. We speculate that preventive interventions and antibacterial treatments should not wait for the appearance of P. aeruginosa or “typical” pathogens that are associated with cystic fibrosis.

Fourth, correcting even one host-defense defect might be beneficial. For example, treating cystic fibrosis with antibiotics may improve a person’s clinical status, even though it does not address mucus abnormalities. Another example is primary ciliary dyskinesia, which completely obliterates one defense — mucociliary transport — yet causes less severe lung disease than cystic fibrosis.74Lung disease might be less severe in primary ciliary dyskinesia because other defenses (e.g., antimicrobial activity) are intact, although differences in the way these diseases impair mucociliary transport might also explain the differing severity.

Fifth, environmental insults may trigger airway disease in the lungs of people with cystic fibrosis. Another “hit” to airways in persons with this disease might come from infections, environmental injuries, or both. Such insults trigger protective responses, including mucus secretion from the submucosal glands. But in cystic fibrosis, what would normally be a protective reflex might further cripple mucociliary transport.

Sixth, cystic fibrosis lung disease may begin in large and small airways. On the basis of histopathological findings in infants who die within weeks to months after birth, it is often thought that this disease begins in small airways. However, rapidly advancing inflammation and remodeling confound interpretation about the initiating location. Histopathological studies of older pigs with cystic fibrosis have detected disease in both large and small airways.26,27,29 Large airways have antibacterial and mucociliary transport defects at birth, which suggests that they are a susceptible site for the onset of disease. However, small airways also express CFTR,75 they probably have defective antibacterial activity, and mucociliary transport in these airways might be impaired by goblet cell–derived mucus. Thus, small airways may also be an initial site of clinical abnormalities. Another consideration is that the total area of small airways is much greater than that of large airways, and thus if physiological defects in both airways were equal on a per-square-meter basis, small airways would be overrepresented.

Seventh, infants with cystic fibrosis may have congenital airway defects. The airway and nasal sinus defects might affect disease progression and complicate assessments. For example, if air trapping is due in part to a congenital defect, rather than to inflammation and abnormal mucus alone, attempting to “treat” on the basis of the appearance of air trapping might not be entirely appropriate.

Eighth, we need better assays of early cystic fibrosis airway disease in humans. Sensitive assays could potentially identify and quantify early host-defense defects and track disease progression and therapeutic interventions. Studies in animal models suggest that assays of the pH of airway-surface liquid, antimicrobial activity, or mucociliary transport could be informative, especially if they are sensitive. For example, the development of methods that assay mucociliary transport in humans with the data granularity achieved in pigs could transform pulmonary imaging of mucociliary transport in cystic fibrosis and possibly other airway diseases.

Finally, these discoveries in cystic fibrosis may also have implications for other diseases. First, they emphasize the value of an animal model that replicates human disease. Second, they highlight the importance of investigating disease at its genesis and before the onset of secondary manifestations. Manifestations of advanced disease may not reflect the initiating events, and without such knowledge, treatments and preventions may not be as effective as they could be. Pulmonary fibrosis is perhaps another respiratory disease in which investigation before clinical manifestations could be revealing. Third, multiple, partial, perhaps even subtle impairments, or “hits,” can have a profound effect. That concept may be relevant to more common pulmonary diseases such as asthma and chronic obstructive pulmonary disease, as well as to nonrespiratory diseases.