Pivotal Role of the 5-Lipoxygenase Pathway in Lung Injury after Experimental Sepsis

Abstract

Postsepsis lung injury is a common clinical problem associated with significant morbidity and mortality. Leukotrienes (LTs) are important lipid mediators of infection and inflammation derived from the 5-lipoxygenase (5-LO) metabolism of arachidonate with the potential to contribute to lung damage after sepsis. To test the hypothesis that LTs are mediators of lung injury after sepsis, we assessed lung structure, inflammatory mediators, and mechanical changes after cecal ligation and puncture surgery in wild-type (WT) and 5-LO knockout (5-LO 2/2 ) mice and in WT mice treated with a pharmacologic LT synthesis inhibitor (MK886) and LT receptor antagonists (CP105,696 and montelukast). Sixteen hours after surgery, WT animals exhibited severe lung injury (by histological analysis), substantial mechanical impairment (i.e., an increase in static lung elastance), an increase in neutrophil infiltration, and high levels of LTB 4 , cysteinyl-LTs (cys-LTs), prostaglandin E 2 , IL-1b, IL-6, IL-10, IL-17, KC (CXCL1), and monocyte chemotactic protein-1 (CCL2) in lung tissue and plasma. 5-LO 2/2 mice and WT mice treated with a pharmacologic 5-LO inhibitor were significantly protected from lung inflammation and injury. Selective antagonists for BLT1 or cys-LT1, the high-affinity receptors for LTB 4 and cysLTs, respectively, were insufficient to provide protection when used alone. These results point to an important role for 5-LO products in sepsis-induced lung injury and suggest that the use of 5-LO inhibitors may be of therapeutic benefit clinically.

Eicosanoids in tissue repair

“…In addition to 5‐LOX, the synthesis of bioactive LTs [LTB 4 and cysteinyl LTs (cysLTs, LTC 4 , LTD 4 , LTE 4 )] requires the enzymes LTA 4 hydrolase (LTA 4 H) and LTC 4 synthase (LTC 4 S). During injury, LT‐biosynthetic enzymes are induced, resulting in increased levels of both LTB 4 and cysLTs in damaged tissues such as the lung or skin . In addition to the COX and 5‐LOX pathways, AA can be metabolized by 12‐ or 15‐LOX enzymes, which are expressed by multiple cell types including myeloid cells and stromal cells.…”

“…In particular, 5‐LOX deficiency or pharmacological targeting of the 5‐LOX pathway resulted in accelerated cutaneous healing, likely by reducing the production of reactive oxygen species (ROS) as well as of proinflammatory cytokines and chemokines in wounded skin . Similarly, 5‐LOX‐deficient mice and mice treated with LT‐modifying drugs were protected against acute inflammatory lung injury in a model of bacterial sepsis . However, these studies also suggested that in addition to the LTB 4 ‐BLT1 axis, cysteinyl LTs contributed to 5‐LOX‐driven inflammatory tissue damage and aberrant tissue repair.…”

“…During injury, LTbiosynthetic enzymes are induced, resulting in increased levels of both LTB 4 and cysLTs in damaged tissues such as the lung or skin. 17 In addition to the COX and 5-LOX pathways, AA can be metabolized by 12-or 15-LOX enzymes, which are expressed by multiple cell types including myeloid cells and stromal cells. 12-/15-LOX metabolites, which are produced during tissue damage and repair include 12-and 15-HETE as well as antiinflammatory LXs.…”

Too much of a good thing: How modulating LTB 4 actions restore host defense in homeostasis or disease

“…5-LO −/− mice or pharmacological inhibition of BLT1 actions protect mice during cecum ligation and puncture (CLP). 5-LO −/− and WT mice treated with a LT synthesis inhibitor have drastically lower levels of neutrophil infiltrates and lower levels of inflammatory cytokines such as IL-1β [84]. During CLP-induced sepsis, treatment with the BLT1 antagonist U-75302 decreases lung injury [85] as evidenced by decreased neutrophil recruitment.…”

α-Tocopherol transfer protein mediates protective hypercapnia in murine ventilator-induced lung injury

“…In other models of lung injury, antagonism of 5-LOX is protective; for example, pharmacological inhibition and gene knockout of 5-LOX protect against murine VILI,18 and in murine sepsis KO of the 5-LOX gene (or inhibition of the enzyme) provided more protection than use of leukotriene receptor antagonists (eg, Montelukast) 34. Antagonism of LTB4 is also effective in lung injury caused by haemorrhagic shock35 or in carrageenan-induced pleurisy 36…”