Of those trauma victims that survive the golden hours immediately following injury, upwards of 50% of these individuals develop some form of multiple organ failure (MODS). This occurs despite the provision of seemingly adequate fluid resuscitation, specific antibiotics, aggressive operative intervention, nutritional support and recently, antibodies to endotoxin as well as various anti-cytokine therapies. In this respect, acute lung injury is reported to be one of the most common forms of organ dysfunction in these individuals. Findings from a number of studies suggest """"""""primed"""""""" neutrophils potentially play a key role in mediating this injury. Active suppression of neutrophil apoptotic death is thought to be a central aspect in the progression toward this pathological outcome. This implies that pro-apoptotic therapies might be efficacious. Alternatively, studies of lymphocytes in both septic and traumatized patients/animals indicate an increase in apoptosis in those cell populations and show that experimental anti-apoptotic therapies seem salutary. This raises important concerns about the design of pro- and/or anti-apoptotic therapies being considered for trauma patients. To address this controversy, we will test the hypothesis that the anti-apoptotic mechanisms shown to be beneficial in a clinically relevant model of sepsis, in which acute lung injury appears to be a minor pathological component, may prove to be deleterious in a model where acute lung injury is evident, such as hypotensive shock followed by septic challenge. To test this hypothesis, we have designed four Aims to examine the contribution of the neutrophils' apoptotic process to the development of acute lung injury by using selected knockout/transgenic mice as well as pharmacological interventions directed at genes or mediators thought to be involved in the regulation of A (sub o). The capacity of neutrophils, from mice of differing A (sub o) gene backgrounds and or inhibitor treatments, to produce acute lung injury will also be assessed by both PMN deletional and PMN add-back approaches, as will the role ofmacrophage/ lymphocytes in mediating the development of this state. It is our firm belief that the results of these studies will provide information that will not only allow us to better understand the pathobiology of acute lung injury but also its attenuation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Harabin, Andrea L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rhode Island Hospital
United States
Zip Code
Bai, Jianwen; Tang, Lunxian; Lomas-Neira, Joanne et al. (2015) TAT-SNAP-23 treatment inhibits the priming of neutrophil functions contributing to shock and/or sepsis-induced extra-pulmonary acute lung injury. Innate Immun 21:42-54
Ayala, Alfred; Elphick, Gwendolyn F; Kim, Ye Sul et al. (2014) Sepsis-induced potentiation of peritoneal macrophage migration is mitigated by programmed cell death receptor-1 gene deficiency. J Innate Immun 6:325-38
Lomas-Neira, Joanne; Perl, Mario; Venet, Fabienne et al. (2012) The role and source of tumor necrosis factor-ýý in hemorrhage-induced priming for septic lung injury. Shock 37:611-20
Monaghan, Sean F; Thakkar, Rajan K; Heffernan, Daithi S et al. (2012) Mechanisms of indirect acute lung injury: a novel role for the coinhibitory receptor, programmed death-1. Ann Surg 255:158-64
Thakkar, Rajan K; Chung, Chun-Shiang; Chen, Yaping et al. (2011) Local tissue expression of the cell death ligand, fas ligand, plays a central role in the development of extrapulmonary acute lung injury. Shock 36:138-43
Perl, Mario; Lomas-Neira, Joanne; Venet, Fabienne et al. (2011) Pathogenesis of indirect (secondary) acute lung injury. Expert Rev Respir Med 5:115-26
Perl, Mario; Chung, Chun-Shiang; Perl, Ulrike et al. (2010) Therapeutic accessibility of caspase-mediated cell death as a key pathomechanism in indirect acute lung injury. Crit Care Med 38:1179-86
Venet, Fabienne; Huang, Xin; Chung, Chun-Shiang et al. (2010) Plasmacytoid dendritic cells control lung inflammation and monocyte recruitment in indirect acute lung injury in mice. Am J Pathol 176:764-73
Huang, Xin; Venet, Fabienne; Wang, Yvonne L et al. (2009) PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A 106:6303-8
Venet, Fabienne; Chung, Chun-Shiang; Huang, Xin et al. (2009) Lymphocytes in the development of lung inflammation: a role for regulatory CD4+ T cells in indirect pulmonary lung injury. J Immunol 183:3472-80

Showing the most recent 10 out of 26 publications