Systemic Inflammation and Fracture healing

Noer Kamila 030.08.182 FK Trisakti / Dept. Bedah RSUD Bekasi

Abstract
Apart from their main role in the host defense against pathogens, leukocytes are also essential for bone repair, as fracture healing is initiated and directed by a physiological inflammatory response.

Introduction
Systemic inflammation, which is characterized by leukocytosis, priming of leukocytes, and systemic release of cytokines, is typically induced in trauma patients within 24 h after admission

Normal Fracture Healing

The concentration of leukocytes within the fracture hematoma remains similar to their concentration in the peripheral circulation for several hours after injury [9]. Within 24 h, however, there is a major influx of neutrophils into the fracture hematoma, making neutrophils the predominate leukocyte within the fracture hematoma [10]. Hereafter, they become replaced by macrophages [11]. Recruited neutrophils are thought to mediate this switch by producing several macrophage chemoattractants, such as MCP-1, also known as CCL2, and IL-6 [12, 13]. After this macrophage phase, T-lymphocytes are selectively recruited into the fracture hematoma and subsequent granulation tissue, whereas practically no B-lymphocytes are found at any stage of fracture healing

Systemic inflammation and fracture healing

Tissue injury leads to the release of endogenous damage-associated molecular patterns that activate innate immune cells [32]. Activation of the immune system is associated with an increased heart rate and respiratory rate and an increased or decreased body temperature, and leukocyte count [4]

 The increased leukocyte count is established predominantly by the rapid release of neutrophils from the bone marrow into the peripheral circulation which leads to a functionally heterogeneous neutrophil compartment that consists of young, banded neutrophils with a refractory phenotype and segmented neutrophils with a primed phenotype

 Neutrophils form the first natural immunological defense against pathogens and are involved in debridement of injured tissue. These cells are relatively short-lived and circulate for several days

 Neutrophils become preactivated by several factors that are up-regulated after severe trauma These priming factors include TNF-, IL-8, and LPS [35]

This implies that neutrophils may stimulate chondrogenesis and inhibit osteogenesis An increased or prolonged influx of neutrophils into the fracture hematoma during systemic inflammation may therefore impair fracture healing through overstimulation of chondrogenesis and inhibition of osteogenesis

 FN- and LPS exposure induces a classically activated, proinflammatory phenotype of macrophages, and IL-4 or IL-13 induces an alternatively activated, regenerative phenotype

 The finding that macrophages, which were exposed to LPS, lose their ability to stimulate osteogenic differentiation of MSCs in vitro

 It has been shown that delta/gamma T cells play an important role in the recruitment of inflammatory cells toward inflammatory sites The finding that delta/gamma T cells exhibit increased expression of activation markers during systemic inflammation

 n summary, systemic inflammation induces several changes in leukocyte characteristics, such as neutrophil priming [37, 38], altered monocyte differentiation [44], T-lymphocyte unresponsiveness [45, 46], and increased / T cell activation [52].

 The inflammatory phase of fracture healing not only initiates but also directs downstream processes of bone repair, and disruption of this phase by systemic inflammation or by local hyperinflammation has been shown to impair fracture healing. The mechanism through which systemic inflammation impairs fracture healing, however, remains unknown.