Goats without Prion Protein Display Enhanced Proinflammatory Pulmonary Signaling and Extracellular Matrix Remodeling upon Systemic Lipopolysaccharide Challenge.

A naturally occurring mutation in the gene of Norwegian dairy goats terminates synthesis of the cellular prion protein (PrP), rendering homozygous goats () devoid of the protein. Although PrP has been extensively studied, particularly in the central nervous system, the biological role of PrP remains incompletely understood. Here, we examined whether loss of PrP affects the initial stage of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Acute pulmonary inflammation was induced by intravenous injection of LPS ( O26:B6) in 16 goats (8 and 8 ). A control group of 10 goats (5 and 5 ) received sterile saline. Systemic LPS challenge induced sepsis-like clinical signs including tachypnea and respiratory distress. Microscopic examination of lungs revealed multifocal areas with alveolar hemorrhages, edema, neutrophil infiltration, and higher numbers of alveolar macrophages, with no significant differences between genotypes. A total of 432 () and 596 () genes were differentially expressed compared with the saline control of the matching genotype. When assigned to gene ontology categories, biological processes involved in remodeling of the extracellular matrix (ECM), were exclusively enriched in PrP-deficient goats. These genes included a range of collagen-encoding genes, and proteases such as matrix metalloproteinases () and cathepsins. Several proinflammatory upstream regulators (TNF-α, interleukin-1β, IFN-γ) showed increased activation scores in goats devoid of PrP. In conclusion, LPS challenge induced marked alterations in the lung tissue transcriptome that corresponded with histopathological and clinical findings in both genotypes. The increased activation of upstream inflammatory regulators and enrichment of ECM components could reflect increased inflammation in the absence of PrP. Further studies are required to elucidate whether these alterations may affect the later reparative phase of ALI.