Antimicrobial effects of nitric oxide in murine models of Klebsiella pneumonia
Steffen B. Wiegand,
Lisa Traeger,
Huan K. Nguyen,
Kaitlyn R. Rouillard,
Anna Fischbach,
Francesco Zadek,
Fumito Ichinose,
Mark H. Schoenfisch,
Ryan W. Carroll,
Donald B. Bloch,
Warren M. Zapol
Affiliations
Steffen B. Wiegand
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA
Lisa Traeger
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA
Huan K. Nguyen
Department of Chemistry, University of North Carolina at Chapel Hill, 125 South Rd, Chapel Hill, NC, 27514, USA
Kaitlyn R. Rouillard
Department of Chemistry, University of North Carolina at Chapel Hill, 125 South Rd, Chapel Hill, NC, 27514, USA
Anna Fischbach
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA
Francesco Zadek
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA
Fumito Ichinose
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA
Mark H. Schoenfisch
Department of Chemistry, University of North Carolina at Chapel Hill, 125 South Rd, Chapel Hill, NC, 27514, USA
Ryan W. Carroll
Department of Pediatric Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA
Donald B. Bloch
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA; Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA
Warren M. Zapol
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA, 02114, USA; Corresponding author. Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine 55 Fruit Str., Boston, MA, 02114, USA.
Rationale: Inhalation of nitric oxide (NO) exerts selective pulmonary vasodilation. Nitric oxide also has an antimicrobial effect on a broad spectrum of pathogenic viruses, bacteria and fungi. Objectives: The aim of this study was to investigate the effect of inhaled NO on bacterial burden and disease outcome in a murine model of Klebsiella pneumonia. Methods: Mice were infected with Klebsiella pneumoniae and inhaled either air alone, air mixed with constant levels of NO (at 80, 160, or 200 parts per million (ppm)) or air intermittently mixed with high dose NO (300 ppm). Forty-eight hours after airway inoculation, the number of viable bacteria in lung, spleen and blood was determined. The extent of infiltration of the lungs by inflammatory cells and the level of myeloperoxidase activity in the lungs were measured. Atomic force microscopy was used to investigate a possible mechanism by which nitric oxide exerts a bactericidal effect. Measurements and main results: Compared to control animals infected with K. pneumoniae and breathed air alone, intermittent breathing of NO (300 ppm) reduced viable bacterial counts in lung and spleen tissue. Inhaled NO reduced infection-induced lung inflammation and improved overall survival of mice. NO destroyed the cell wall of K. pneumoniae and killed multiple-drug resistant K. pneumoniae in-vitro. Conclusions: Intermittent administration of high dose NO may be an effective approach to the treatment of pneumonia caused by K. pneumoniae.
