Traumatic brain injury is known to cause several secondary effects, which lead to multiple organ dysfunction syndrome. An acute systemic inflammatory response seems to play an integral role in the development of such complications providing the potential for massive secondary injury. We show that a contusion injury to the rat brain causes large migration of inflammatory cells (especially macrophages and neutrophils) in the major airways and alveolar spaces at 24 h post-injury, which is associated with enhanced pulmonary leukotriene B4 (LTB4) production within the lung. However, by 2 weeks after injury, a temporal switch occurs and the resolution of inflammation is underway. We provide evidence that 5-lipoxygenase and Cytochrome P450 4Fs (CYP4Fs), the respective enzymes responsible for LTB4 synthesis and breakdown, play crucial roles in setting the cellular concentration of LTB4. Activation of LTB4 breakdown via induction of CYP4Fs, predominantly in the lung tissue, serves as an endogenous signal to ameliorate further secondary damage. In addition, we show that CYP4Fs are localized primarily in the airways and pulmonary endothelium. Given the fact that adherence to the microvascular endothelium is an initial step in neutrophil diapedesis, the temporally regulated LTB4 clearance in the endothelium presents a novel focus for treatment of pulmonary inflammation after injury.