The two faces of inflammation during fracture healing

Abstract

Calor (increased heat), rubor (redness), tumor (swelling) and dolor (pain) are the four cardinal signs of inflammation, which were described by Celsus during the first century. Later, a fifth sign was added to Celsus tetrad, which is functio laesa (disturbance or loss of function). It is well known that inflammation, which means “set on fire” in Latin, can inflict collateral damage to a variety of processes important for the homeostasis within our body and thereby disturb their function. Inflammation therefore has two faces: it is designed to limit further damage and induce healing, but it is also a major driver of complications and fatal outcomes. Modulating the inflammatory response may be a powerful tool to augment tissue regeneration and prevent complications, especially in high-risk individuals, such as patients with multiple injuries. In order to modulate inflammation, it is essential to first understand both of its faces. Bone injury is one of the most common injuries that humans experience. We, therefore, aimed to clarify how inflammation contributes to bone repair, how systemic inflammation can impair fracture healing and finally, we identified a receptor on neutrophils, which is involved in chemotaxis of neutrophils towards the human fracture hematoma (FH) in vitro. Our data suggests that neutrophils contribute to fracture healing by synthesizing a fibronectin+ extracellular matrix within the fracture hematoma (FH) rapidly after injury. The current literature suggests that major trauma may induce an undesirable systemic inflammatory response that impairs fracture healing, potentially through an increased influx of neutrophils into the FH. We found that the systemic response to trauma differs between multitrauma patients with normal and impaired fracture healing of the tibia and femur. The difference in response that we found may represent increased extravasation of inflammatory cells towards sites of injury or trauma-induced inhibition of a myeloid bone marrow response. Our additional study showed that high neutrophil concentrations negatively affect synthesis of extracellular matrix by bone marrow derived multipotent stromal cells in vitro. This finding could explain how increased influx of neutrophils into the FH impairs bone healing after severe injury. Blocking the C5a-receptor in neutrophils with CHIPSΔ1F could inhibit chemotaxis of neutrophils towards the FH in vitro. Future studies should further clarify how inflammatory cells contribute to fracture healing. These studies may contribute to the development of therapies that augment tissue regeneration and prevent impairment of bone healing after major trauma.