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Induction of local inflammation by recombinant human platelet factor 4 in the mouse
R J Sharpe1, G F Murphy, D Whitaker
1Repligen Corporation, Cambridge, Massachusetts 02139.
Abstract:
Platelet factor 4 (PF-4) has been shown to be chemotactic for neutrophils and monocytes in vitro. To assess whether these observations have in vivo relevance, we tested the ability of recombinant human PF-4 (rPF-4) to induce acute and chronic dermal inflammation in the mouse. When injected as a single dose intradermally, rPF-4 induced an acute inflammatory response that peaked at 6 to 12 hr and which resolved by 36 hr. Injection of an equivalent amount of cytochrome c, buffer alone, or an amino-terminal PF-4 peptide failed to elicit a significant inflammatory response; however, the carboxy-terminal PF-4 peptide retained proinflammatory properties. The inflammatory infiltrate induced by a single injection of either rPF-4 or the 41 amino acid carboxy-terminal peptide was composed of neutrophils and smaller numbers of mononuclear cells. Repeated injection of rPF-4 resulted in nearly equal numbers of neutrophils and mononuclear cells. Moreover, marked dermal fibrosis developed after only 5 days of daily injection of rPF-4. Although relatively high concentrations of rPF-4 were required to elicit an inflammatory response, these concentrations may be locally attainable during platelet aggregation. Our findings thus support the hypothesis that PF-4 may contribute to the development of inflammatory responses at sites of platelet aggregation.
Insights
Platelet factor 4 (PF-4) can cause acute and chronic skin inflammation and fibrosis in mice. This suggests PF-4 may play a role in inflammatory responses at sites of platelet aggregation.
Area of Science:
- Immunology
- Dermatology
- Hematology
Background:
- Platelet factor 4 (PF-4) is known to attract neutrophils and monocytes in vitro.
- The in vivo relevance of PF-4's inflammatory properties requires further investigation.
Purpose of the Study:
- To determine if recombinant human PF-4 (rPF-4) can induce acute and chronic dermal inflammation in a mouse model.
- To identify which parts of the PF-4 molecule are responsible for its inflammatory effects.
Main Methods:
- Intradermal injection of rPF-4, cytochrome c, buffer, and PF-4 peptides into mice.
- Assessment of acute and chronic dermal inflammatory responses, including cellular infiltrate and fibrosis.
- Histological analysis of skin tissue.
Main Results:
- Single intradermal rPF-4 injection induced acute inflammation (neutrophils and monocytes) peaking at 6-12 hours.
- The carboxy-terminal PF-4 peptide, but not the amino-terminal peptide, retained proinflammatory properties.
- Repeated rPF-4 injections led to chronic inflammation with equal neutrophil and mononuclear cell infiltration and significant dermal fibrosis within 5 days.
Conclusions:
- PF-4, particularly its carboxy-terminal region, can induce both acute and chronic dermal inflammation and fibrosis in vivo.
- These findings support the hypothesis that PF-4 contributes to inflammatory responses at sites of platelet aggregation.
- While high concentrations are needed, local concentrations may be achieved during platelet aggregation.