C. S. Mott Children's Hospital

University of Michigan Health System

Pulmonology: Research

Wan C. Tsai, M.D.

TSAI04G0 (Tsai, PI) 4/10/04-3/31/06
Cystic Fibrosis Foundation Research Grant
“Effect of macrolides on neutrophil recruitment in Pseudomonas endobronchial infection”
Role: Principal Investigator
This application addresses the mechanism by which inhibits azithromycin inhibits neutrophil
recruitment in response to Pseudomonas aeruginosa infection.

CXC Chemokines in Pseudomonas Airway Infection

Persistent airway (endobronchial) infection due to mucoid and nonmucoid strains of Pseudomonas aeruginosa is a common and devastating complication of airway diseases such as cystic fibrosis and bronchiectasis, resulting in progressive airway destruction that carries a high mortality, despite the best available therapy. Dr. Tsai's broad, long-term objective is to define the mechanism of recruitment and activation of immune cells in Pseudomonas endobronchial infection. The central hypothesis of this work is that the influx of neutrophils into the airways in Pseudomonas endobronchial infection is mediated by a family of chemotactic cytokines, the ELR(+) CXC chemokines, and that manipulation of these ligands or their receptor will impact the outcome of this infection.

To test this hypothesis, Dr. Tsai and her colleagues are: 1) Examining the time-course and magnitude of expression of the ELR(+) CXC chemokines and their receptor, CXCR2, in mice challenged with intratracheal mucoid P. aeruginosa agar beads; 2) Determining the contribution of specific ELR(+) CXC chemokines, and their shared receptor CXCR2 in mucoid Pseudomonas endobronchial infection by evaluating the outcome of infection in animals passively immunized with neutralizing antibodies against CXCR2 or selected ligands; and 3) Evaluating the effect of airway-specific transgenic expression of relevant ELR(+) CXC chemokines in mucoid Pseudomonas endobronchial infection, by examining the outcome of infection in lung-specific chemokine transgenic animals and animals transiently expressing the chemokine transgene in the airway using adeno-associated viral gene therapy. This work is funded by the National Institutes of Health.

Recent Publications:

  1. Tsai WC, Strieter RM, Mehrad B, Newstead MW, Zeng X, Standiford TJ. CXC Chemokine Receptor CXCR2 is essential for protective innate host response in murine Pseudomonas aeruginosa pneumonia. Infect Immun 68: 4289-4296, 2000.
  2. Tateda K, Moore T A, Newstead MW, Tsai WC, Zeng X, Deng JC, Chen G, Reddy R, Yamaguchi K, Standiford TJ. Chemokine-dependent neutrophil recruitment in a murine model of legionella pneumonia: Potential role of neutrophils as immunoregulatory cells Infect Immun 69: 2017-2024, 2001.
  3. Reddy RC, Chen GH, Tateda K, Tsai WC, Phare SM, Mancuso P, Peters-Golden M, Standiford TJ. COX-2 inhibition improves early survival in murine endotoxemia but fails to decrease mortality in bacterial peritonitis. Am J Physiol Lung Cell Mol Physiol 281: L537-L543, 2001.
  4. Zeng X, Moore TA, Newstead MW, Hernandez-Alcoceba R, Tsai WC, Standiford TJ. Intrapulmonary expression of macrophage inflammatory protein 1alpha (CCL3) induces neutrophil and NK cell accumulation and stimulates innate immunity in murine bacterial pneumonia. Infect Immun. 71: 1306-15, 2003.