The body needs mechanisms to keep acute inflammation in check. Much less is known about these regulatory mechanisms than about the mechanisms initiating and amplifying inflammation. A few examples of how regulatory mechanisms influence the outcome of lung infections are presented here.
One such braking strategy is to limit NF-κB activity. The NF-κB protein p50 has multiple functions, which include curbing the transcription of genes with NF-κB–binding sites in their promoters. 43
During bacterial pneumonia in mice, a deficiency of p50 increases cytokine expression and exacerbates lung injury.82
Thus, p50 normally functions to prevent excess cytokines and inflammatory injury during pneumonia.
Another mechanism is interference with signaling from pattern-recognition receptors. The interleukin-1 receptor–associated kinase (IRAK)–like molecule (IRAK-M) inhibits IRAK-mediated signaling from the pattern-recognition and cytokine receptors that activate NF-κB. Sepsis induces IRAK-M in mouse alveolar macrophages, and this protein decreases cytokine expression and compromises pulmonary host defense.83
IRAK-M may therefore contribute to the susceptibility of patients with sepsis to nosocomial pneumonia. Other regulatory molecules inhibit pattern-recognition–receptor signaling indirectly. For example, carbon monoxide generated by heme oxygenase-1 inhibits signaling from transmembrane pattern-recognition receptors.84
A deficiency of heme oxygenase-1 increases, whereas its overexpression decreases, inflammation and injury induced by bacteria and influenza virus in mouse lungs.85–87
Prevention of injury is probably due to both the antiinflammatory and the tissue-protective activities of heme oxygenase-1.
The signal transducer and activator of transcription 3 (STAT3) also has antiinflammatory and tissue-protective effects. Mutations in STAT3 result in the hyper-IgE syndrome, which is characterized by recurrent and severe lung infections.88
This transcription factor is activated in macrophages and epithelial cells during acute pulmonary inflammation.89
Macrophage STAT3 mediates antiinflammatory responses induced by the cytokine interleukin-10,90
which compromises host defense but limits lung injury during pneumonia. 91–94
Epithelial-cell STAT3 is essential in preventing lung injury during infection.95
The signals that activate epithelial-cell STAT3 are uncertain, but are not likely to include interleukin-10. STAT3 activation in the lungs during E. coli
infection depends partially on interleukin-6, which is essential for overcoming bacterial pneumonia.96
(prostacyclin) is generated during respiratory syncytial virus infection and has protective activities that may be mediated by antiinflammatory effects on dendritic cells.97,98
In addition to having antiinflammatory activities, other lipids, including lipoxins, resolvins, and protectins, help return inflamed tissues to health.99
During and after pneumonia, the return of the architecture of a lung lobe from complete consolidation to a seemingly normal state is remarkable. Unfortunately, few if any studies have reported the mechanisms underlying this process of resolution during lung infection, so the presumed role of lipids must at present be based on extrapolation.