© 2003 American Thoracic Society
The Nose, Nitric Oxide, and Paranasal SinusesThe Outpost of Pulmonary Antiinfectious Defenses?Réanimation Chirurgicale Pierre Viars Hôpital Pitié-Salpétrière Paris, France In this issue of AJRCCM (pp. 281–286), Deja and coworkers (1) provide evidence that an inducible form of nitric oxide (NO) synthase is normally present within cilia and microvilli of the maxillary sinus epithelium. As previously demonstrated in humans and other mammals (2, 3), significant amounts of endogenous NO are continuously released from paranasal sinuses into the nasal airstream and inhaled during tidal ventilation. Physiologically, autoinhaled NO reduces pulmonary shunt (4), is essential for an efficient ciliary activity, and inhibits the growth of viruses and bacteria invading cilia (5). In other words, the paranasal sinuses, the nose, and regionally produced NO can be considered as the first-line host defense of the respiratory tract against inhaled microorganisms. A remarkable result of the study is that simple inflammation of the sinus mucosa, as observed in radiologic maxillary sinusitis, is associated with dramatic inhibition of the expression of the local inducible NO synthase. As a consequence, a substantial decrease in the intracavitary release of endogenous NO is observed, likely resulting in marked impairments of ciliary activity in the maxillary sinus and host defenses. A decrease in nasal NO concentrations was previously reported in patients with chronic or acute maxillary sinusitis and believed to result from the mechanical obstruction of ostia by local edema, nasal congestion, and mucus accumulation within the sinus cavities (6). Using an artful methodology, consisting of an initial drainage of the maxillary cavity followed by a continuous suctioning through a surgically inserted catheter, Deja and coworkers have provided evidence of major inhibition of the intracavitary release of endogenous NO (1). Interestingly, most of the maxillary sinusitis detected radiologically in the study was not infectious sinusitis, as attested by histologic biopsies, the nature of inflammatory cells retrieved in the maxillary content, and microbiological cultures. All patients, however, had criteria of generalized sepsis. An attractive hypothesis raised by the authors is that sepsis induces a silent inflammation of the paranasal sinus mucosa, impairing endogenous NO synthesis and thereby local host defenses against microbial invaders. In addition, the marked decrease in the intracavitary concentrations of endogenous NO likely induces vasoconstriction of mucosal vessels and intravascular platelet aggregation (7, 8), two factors tending to compromise mucosal circulation and promote additional impairment of maxillary sinus defenses against infection. It has to be pointed out that generalized sepsis, well known for stimulating numerous tissue-inducible NO synthases, inhibits the NO metabolic pathway at the maxillary level (9). Reduced nasal NO concentrations have been reported in acute and chronic sinusitis, cystic fibrosis, primary ciliary dysfunction, chronic cough, and exposure to tobacco or alcohol—all conditions being characterized by histologic alterations of ciliary mucosa of the upper airways (6). According to the location of inducible NO synthase expression in cilia and microvilli of the luminal maxillary sinus epithelium, it would not be surprising to find similar locations in other vibratile epithelia of the upper airways. Evidence continues to accumulate showing that endogenous NO plays a pivotal, subtle, and ubiquitous role in physiologic homeostasis: an insufficient production of paranasal NO resulting from sepsis is probably as deleterious for the maxillary sinus ciliary and antibacterial functions (1) as is an excessive production of endogenous NO for the cardiovascular system during septic shock (9). What is the clinical relevance of these results? Do they have a direct therapeutic impact for critically ill patients receiving mechanical ventilation? Over the past 10 years, compelling evidence has demonstrated that the paranasal sinuses are frequent and silent sources of nosocomial infections in mechanically ventilated patients (10, 11). The major risk factor is the presence of endotracheal and/or gastric tubes within the nares. Nevertheless, the positioning of foreign bodies via the oral route does not reduce the incidence of infectious maxillary sinusitis to zero (12). The study by Deja and coworkers provides an explanation: generalized sepsis probably impairs maxillary ciliary function and antibacterial defenses, thereby producing mucosal accumulation, cavity obstruction, and superinfection. As a consequence, the paranasal sinuses become a reservoir of microorganisms from which bacterial seeding of the distal lung parenchyma takes place (12, 13). Adopting a clinical strategy based on a systematic search and treatment of infectious maxillary sinusitis reduces mortality rate and the incidence of ventilator-associated bronchopneumonia in critically ill patients receiving prolonged mechanical ventilation (14). Classically, it is recommended that only infectious maxillary sinusitis should be aggressively treated by a surgical fenestration or a transmaxillary antrum drainage; intravenous administration of antibiotics in itself is insufficient to get rid of the infection within the maxillary cavities (15). In fact, the study by Deja and coworkers suggests that radiologic maxillary sinusitis may also benefit from such treatment. Because sepsis-induced inhibition of maxillary inducible NO synthase activity impairs ciliary activity and local antibacterial defenses, it may promote mucus accumulation and rapid superinfection. This vicious circle could explains why, very frequently, radiologic maxillary sinusitis is rapidly transformed into a true infection of the maxillary cavity, forming not only a reservoir of nosocomial microorganisms for the lung but also a silent and frequently under-diagnosed focus of deep infection. If this concept is true, then early and prolonged drainage of radiologic maxillary sinusitis should be efficient for preventing maxillary cavity superinfection and eliminating one of the reasons why the lung is a target organ for nosocomial microorganisms in ventilated critically ill patients (16). Further clinical studies are required to substantiate this hypothesis. 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