Eicosanoid regulation of pulmonary innate immunity post-hematopoietic stem cell transplantation

Abstract

Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for a number of malignant and inherited disorders. However, the efficacy of this therapy is limited by a number of serious infectious and noninfectious complications. Pulmonary infections represent a significant cause of morbidity and mortality post-HSCT and can occur both pre-and post-hematopoietic reconstitution. Susceptibility to Gram-negative bacterial infections despite full hematopoietic engraftment suggests that innate immunity remains impaired months to years post-HSCT. This review will describe the process and complications of HSCT and will summarize what is known about innate immune reconstitution post-HSCT. Data from the literature as well as our own laboratory will be presented to suggest that an eicosanoid imbalance characterized by overproduction of prostaglandins and under-production of leukotrienes leads to impaired lung phagocyte function post-HSCT. Of therapeutic interest, strategies which limit production of prostaglandins can improve pulmonary host defense in animal HSCT models, which suggests that this may also be beneficial for human HSCT recipients.

Comparison of Conditioning Regimens for Alveolar Macrophage Reconstitution and Innate Immune Function Post Bone Marrow Transplant

“…Pulmonary complications, particularly infections remain the leading cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplant despite advances in prophylaxis [2,3,7]. This is likely due, in part, to innate immune defects noted in AMs of patients post transplant [10].…”

“…Unfortunately, patients who have undergone stem cell transplantation are at risk for pulmonary infections [2][3][4][5] and pneumonia remains the leading infectious cause of death following stem cell transplantation despite the implementation of numerous prophylactic strategies and advances in diagnosis and treatment [6]. These transplant patients manifest increased susceptibility to infections for periods of time (months to years) post transplantation, extending long after engraftment of leukocytes from donor sources [2,7].…”

“…Unfortunately, patients who have undergone stem cell transplantation are at risk for pulmonary infections [2][3][4][5] and pneumonia remains the leading infectious cause of death following stem cell transplantation despite the implementation of numerous prophylactic strategies and advances in diagnosis and treatment [6]. These transplant patients manifest increased susceptibility to infections for periods of time (months to years) post transplantation, extending long after engraftment of leukocytes from donor sources [2,7].We have previously established a murine model of gram-negative bacterial infection following bone marrow transplantation (BMT) and have shown that these mice are more susceptible to pulmonary infection with the gram-negative pathogen Pseudomonas aeruginosa due to defects in innate immune cells. these studies involved 13 Gy of total body irradiation (TBI) followed by reconstitution with 5 × 10 6 whole bone marrow (BM) cells + 1 × 10 6 syngeneic splenic T cells.…”

Phenotype of theCyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

“…All of the above-described phenotypic alterations may well be the result of alterations in the production, catabolism and/or function of eicosanoids: bioactive mediators derived from arachidonic acid via -6 fatty acids (including prostaglandins, prostacyclins, leukotrienes, thromboxanes, hepoxilins, and lipoxins) and bioactive mediators derived from eicosapentaenoic acid and docosahexaenoic acid via -3 fatty acids, (including resolvins, docosatrienes, eoxins, and neuroprotectins). Eicosanoids exert largely unappreciated complex control over virtually all physiological processes: inflammation (Chiang et al, 2005;Leone et al, 2007;Mariotto et al, 2007;Serhan, 2007;Seubert et al, 2007), resolution phase of inflammation (Serhan, 2007), innate immunity (Ballinger et al, 2007), cardiopulmonary and vascular functions (Moreland et al, 2007;Seubert et al, 2007), angiogenesis (Fleming, 2007;Inceoglu et al, 2007), sensor of vascular pO 2 (Sacerdoti et al, 2003), bowel motility (Proctor et al, 1987), regulation of lipid metabolism and insulin sensitivity (Larsen et al, 2007;Nigam et al, 2007;Spector and Norris, 2007), central nervous system functions (Miyata and Roman, 2005;Jakovcevic and Harder, 2007), modulation of non-neuropathic pain (Inceoglu et al, 2007), neurohormone secretion and release (Inceoglu et al, 2007), fibrinolysis (Westlund et al, 1991;Jiang, 2007), inhibition of platelet aggregation (Westlund et al, 1991;Jiang, 2007), reproductive success (Cha et al, 2006;Weems et al, 2006), blastocyst implantation (Cha et al, 2006;Kennedy et al, 2007), early embryonic as well as fetal development (Cha et al, 2006), stimulation of tyrosine phosphorylation (Chen et al, 1998), G protein-si...…”

Paradoxical role of alveolar macrophage-derived granulocyte-macrophage colony-stimulating factor in pulmonary host defense post-bone marrow transplantation

“…Although beneficial in many cases, the success of HSCT is limited due to many serious infectious (31) and noninfectious (10,30,43) complications. Over half of all HSCT patients suffer from pulmonary complications, and nearly onethird of these patients require admission to the intensive care unit (6,31). Pneumonia remains the leading infectious cause of death following transplantation despite the implementation of numerous prophylactic strategies and advances in diagnosis and treatment.…”