Modeling inflammation in the Zebrafish: How a fish can help us understand lung disease

Neutrophilic inflammation is responsible for much of the tissue damage seen in many lung diseases. For resolution of inflammation to occur, neutrophils must die by apoptosis, allowing their recognition and removal by macrophages. The molecular events controlling this important regulatory step are poorly understood, in large part due to the genetic. intractability of the human neutrophil granulocyte. The authors have established a model of inflammation in the Zebrafish, which shares many features of the innate immune system with those of humans. Injury to the Zebrafish tailfin induces a reproducible and quantifiable inflammatory response, which resolves with kinetics similar to mammalian models of neutrophilic inflammation., including pulmonary inflammation. Pharmacological modulation of neutrophil apoptosis can modulate the outcome of experimentally induced inflammation. In addition, the authors have generated a construct that expresses green fluorescent protein under the myeloperoxidase promoter, allowing in vivo visualization of neutrophils during experimentally induced inflammation. The authors are also performing an unbiased forward genetic screen for mutants with defective resolution of inflammation, and to date have identified a number of putative mutants. Further study and characterization of these mutants is underway. The authors have thus established an important experimental link between apoptosis and resolution of inflammation in an in vivo system, and defined an important new model for the study of inflammation resolution. The authors hope that these tools will permit detailed study of the genetic controls of the resolution of inflammation, and provide insights with potential clinical utility.