Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy

Abstract

Objective: Elevated inflammatory cytokine levels have been implicated in the pathogenesis of non-healing chronic venous insufficiency (CVI) ulcers. The goal of this study was to determine the protein levels of a wide range of inflammatory cytokines in untreated CVI ulcer tissue before and after 4 weeks of high-strength compression therapy. These levels were compared to cytokines present in healthy tissue.

Methods: Thirty limbs with untreated CVI and leg ulceration received therapy for 4 weeks with sustained high-compression bandaging at an ambulatory wound center. Biopsies were obtained from healthy and ulcerated tissue before and after therapy. A multiplexed protein assay was used to measure multiple cytokines in a single sample. Patients were designated as rapid or delayed healers based on ulcer surface area change.

Results: The majority of pro-inflammatory cytokine protein levels were elevated in ulcer tissue compared to healthy tissue, and compression therapy significantly reduced these cytokines. TGF-beta1 was upregulated in ulcer tissue following compression therapy. Rapid healing ulcers had significantly higher levels of IL-1alpha, IL-1beta, IFN-gamma, IL-12p40, and granulocyte macrophage colony stimulating factor (GM-CSF) before compression therapy, and IL-1 Ra after therapy. IFN-gamma levels significantly decreased following therapy in the rapidly healing patients.

Conclusion: CVI ulcer healing is associated with a pro-inflammatory environment prior to treatment that reflects metabolically active peri-wound tissue that has the potential to heal. Treatment with compression therapy results in healing that is coupled with reduced pro-inflammatory cytokine levels and higher levels of the anti-inflammatory cytokine IL-1 Ra.

Fig 1

Levels of cytokine in ulcer tissue before and after 4 weeks of compression therapy for ulcers that healed > 40% compared to ulcers that healed < 40% at 4 weeks. A: Interferon-gamma (IFN-γ), B: Interleukin-1α (IL–1α), C: Interleukin-1β (IL-1β), D: Interleukin-1 receptor antagonist (IL-1RA), E: Interleukin-12p40 (IL-12p40), F: Granulocyte macrophage colony stimulating factor (GM-CSF). All levels are expressed in picograms of cytokine per microgram of protein in the tissue biopsy sample. * = statistically significant with P < .05.

Fig 1

Levels of cytokine in ulcer tissue before and after 4 weeks of compression therapy for ulcers that healed > 40% compared to ulcers that healed < 40% at 4 weeks. A: Interferon-gamma (IFN-γ), B: Interleukin-1α (IL–1α), C: Interleukin-1β (IL-1β), D: Interleukin-1 receptor antagonist (IL-1RA), E: Interleukin-12p40 (IL-12p40), F: Granulocyte macrophage colony stimulating factor (GM-CSF). All levels are expressed in picograms of cytokine per microgram of protein in the tissue biopsy sample. * = statistically significant with P < .05.

Fig 1

Levels of cytokine in ulcer tissue before and after 4 weeks of compression therapy for ulcers that healed > 40% compared to ulcers that healed < 40% at 4 weeks. A: Interferon-gamma (IFN-γ), B: Interleukin-1α (IL–1α), C: Interleukin-1β (IL-1β), D: Interleukin-1 receptor antagonist (IL-1RA), E: Interleukin-12p40 (IL-12p40), F: Granulocyte macrophage colony stimulating factor (GM-CSF). All levels are expressed in picograms of cytokine per microgram of protein in the tissue biopsy sample. * = statistically significant with P < .05.

Fig 1

Levels of cytokine in ulcer tissue before and after 4 weeks of compression therapy for ulcers that healed > 40% compared to ulcers that healed < 40% at 4 weeks. A: Interferon-gamma (IFN-γ), B: Interleukin-1α (IL–1α), C: Interleukin-1β (IL-1β), D: Interleukin-1 receptor antagonist (IL-1RA), E: Interleukin-12p40 (IL-12p40), F: Granulocyte macrophage colony stimulating factor (GM-CSF). All levels are expressed in picograms of cytokine per microgram of protein in the tissue biopsy sample. * = statistically significant with P < .05.

Fig 1

Levels of cytokine in ulcer tissue before and after 4 weeks of compression therapy for ulcers that healed > 40% compared to ulcers that healed < 40% at 4 weeks. A: Interferon-gamma (IFN-γ), B: Interleukin-1α (IL–1α), C: Interleukin-1β (IL-1β), D: Interleukin-1 receptor antagonist (IL-1RA), E: Interleukin-12p40 (IL-12p40), F: Granulocyte macrophage colony stimulating factor (GM-CSF). All levels are expressed in picograms of cytokine per microgram of protein in the tissue biopsy sample. * = statistically significant with P < .05.

Fig 1

Levels of cytokine in ulcer tissue before and after 4 weeks of compression therapy for ulcers that healed > 40% compared to ulcers that healed < 40% at 4 weeks. A: Interferon-gamma (IFN-γ), B: Interleukin-1α (IL–1α), C: Interleukin-1β (IL-1β), D: Interleukin-1 receptor antagonist (IL-1RA), E: Interleukin-12p40 (IL-12p40), F: Granulocyte macrophage colony stimulating factor (GM-CSF). All levels are expressed in picograms of cytokine per microgram of protein in the tissue biopsy sample. * = statistically significant with P < .05.