Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair.
T helper 1 responses are typically proinflammatory, while Th2 responses have been considered regulatory. Interestingly, Th2 responses characterize a number of pulmonary diseases, many of which terminate in tissue remodeling and fibrosis. We developed a mouse model using Schistosoma mansoni eggs and cytokine-deficient mice to induce highly polarized Th1- or Th2-type inflammation in the lung. In this study, we examined the pathology and cytokine profiles in Th1- and Th2-polarized environments and used oligonucleotide microarray analysis to decipher the genes responsible for these effects. We further elaborated on the results using IL-10- and IL-13-deficient mice because these cytokines are believed to be the central regulators of Th2-associated pathology. We found that the Th1-polarized mice developed small granulomas with less fibrosis while expressing genes characteristic of tissue damage. Th2-polarized mice, in contrast, formed large granulomas with massive collagen deposition and up-regulated genes associated with wound healing, specifically, arginase, collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of MMP. In addition, several members of the chitinase-like family were up-regulated in the lung following egg challenge. We also developed a method of defining the net collagen deposition using the expression profiles of several collagen, MMP, and tissue inhibitors of MMP genes. We found that Th1-polarized mice did not elaborate collagens or MMPs and therefore did not have a significant capacity for repair in this model. Thus, Th1-mediated inflammation is characterized by tissue damage, while Th2 directs wound healing and fibrosis.
D000208:Acute Disease; D000818:Animals; D000947:Antigens, Helminth / Q000008:administration & dosage / Q000276:immunology; D002478:Cells, Cultured; D002688:Chitinases / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D016130:Immunophenotyping; D008174:Lung Diseases, Parasitic / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010063:Ovum / Q000276:immunology; D012550:Schistosoma mansoni / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D013045:Species Specificity; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014945:Wound Healing / Q000235:genetics / Q000276:immunology*
D000947:Antigens, Helminth; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D002688:Chitinases