Pneumonia remains the leading cause of infectious deaths and yet fundamentally new conceptual models underlying its pathogenesis have not emerged. Patients and mice with bacterial pneumonia have marked elevations of cardiolipin in lung fluid, a rare, mitochondrial-specific phospholipid that potently disrupts surfactant function. Intratracheal cardiolipin in mice recapitulates the clinical phenotype of pneumonia including impaired lung mechanics, modulation of cell survival and cytokine networks, and lobar consolidation. We have identified and characterized the activity of a novel cardiolipin transporter, ATP8b1, a mutant version of which is associated with severe pneumonia in humans and mice. ATP8b1 bound and internalized cardiolipin from extracellular fluid via a basic residue-enriched motif. Administration of cardiolipin binding motif peptide or ATP8b1 gene transfer in mice lessened lung injury and improved survival. The results unveil a new paradigm whereby ATP8b1 is a cardiolipin importer but its capacity to remove cardiolipin from lung fluid is exceeded during inflammation or ATP8b1 inefficiency. This discovery opens the door for new therapeutic strategies directed at modulating cardiolipin levels or its molecular interactions in pneumonia.

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Recent reports postulate that the dual oxidase (DUOX) proteins function as part of a multicomponent oxidative pathway used by the respiratory mucosa to kill bacteria. The other components include epithelial ion transporters, which mediate the secretion of the oxidizable anion thiocyanate (SCN(-)) into airway surface liquid, and lactoperoxidase (LPO), which catalyzes the H(2)O(2)-dependent oxidation of the pseudohalide SCN(-) to yield the antimicrobial molecule hypothiocyanite (OSCN(-)). We hypothesized that this oxidative host defense system is also active against respiratory viruses. We evaluated the activity of oxidized LPO substrates against encapsidated and enveloped viruses. When tested for antiviral properties, the LPO-dependent production of OSCN(-) did not inactivate adenovirus or respiratory syncytial virus (RSV). However, substituting SCN(-) with the alternative LPO substrate iodide (I(-)) resulted in a marked reduction of both adenovirus transduction and RSV titer. Importantly, well-differentiated primary airway epithelia generated sufficient H(2)O(2) to inactivate adenovirus or RSV when LPO and I(-) were supplied. The administration of a single dose of 130 mg of oral potassium iodide to human subjects increased serum I(-) concentrations, and resulted in the accumulation of I(-) in upper airway secretions. These results suggest that the LPO/I(-)/H(2)O(2) system can contribute to airway antiviral defenses. Furthermore, the delivery of I(-) to the airway mucosa may augment innate antiviral immunity.

Interhospital transfers to the medical intensive care unit are patients at high risk for mortality and other adverse outcomes. System-level and patient-level characteristics influence both early and overall hospital mortality rates. These variables should be considered when risk stratifying medical intensive care unit patients and in studying outcomes of care.