? ? Patients who survive sepsis remain highly susceptible to subsequent nosocomial infections, particularly bacterial pneumonia. Alveolar macrophages are functionally impaired following sepsis, characterized by diminished inflammatory responses to endotoxin and reduced antimicrobial activity. While monocyte/macrophage deactivation is one of the key features of sepsis-induced immunosuppression, the precise cellular and molecular pathways that mediate this phenomenon during sepsis are unclear. Given the hyporesponsiveness of septic macrophages to endotoxin, one of the potential mechanisms for sepsis-induced macrophage deactivation may involve the Toll-like receptor (TLR)4 signaling pathways. TLRs are critical for host recognition of microbial pathogens and the generation of an inflammatory innate immune response, lnterleukin-1 receptor associated kinase-M (IRAK-M) has been demonstrated to be a negative regulator of several TLRs, including TLR4, which is the receptor for lipopolysaccharide (LPS). The hypothesis to be tested in this proposal is that the sepsis-induced impairment of TLR4 signaling pathways in alveolar macrophages is mediated by IRAK-M. To test this hypothesis, these studies will employ a murine model of polymicrobial peritonitis-induced sepsis [cecal ligation and puncture (CLP) model] in both wildtype and IRAK-M knockout mice.
The specific aims of this, proposal are to: 1) assess the time-dependent expression of TLR4, CD14, and IRAK-M in alveolar and pulmonary macrophages following CLP; 2) determine the functional significance of IRAK-M on effector cell function and LPS signaling pathways in endotoxin- and sepsis-deactivated alveolar macrophages in vitro; and 3) determine the contribution of IRAK-M to sepsis-induced impairment of lung bacterial clearance in-vivo. Collectively, these studies will enable us to determine if IRAK-M is a relevant mediator of sepsis-induced macrophage deactivation, thereby identifying a potential therapeutic target to reverse the immuno-suppression that occurs in patients with sepsis. ? ? ? ?
| Wang, Tisha; Derhovanessian, Ariss; De Cruz, Sharon et al. (2014) Subsequent infections in survivors of sepsis: epidemiology and outcomes. J Intensive Care Med 29:87-95 |
| Hu, Scott B; Zider, Alexander; Deng, Jane C (2012) When host defense goes awry: Modeling sepsis-induced immunosuppression. Drug Discov Today Dis Models 9:e33-e38 |
| Tian, Xiaoli; Xu, Feng; Lung, Wing Yi et al. (2012) Poly I:C enhances susceptibility to secondary pulmonary infections by gram-positive bacteria. PLoS One 7:e41879 |
| Ghaffari, Amir A; Chow, Edward K; Iyer, Shankar S et al. (2011) Polyinosinic-polycytidylic acid suppresses acetaminophen-induced hepatotoxicity independent of type I interferons and toll-like receptor 3. Hepatology 53:2042-52 |
| Deng, Jane C; Standiford, Theodore J (2011) Growth factors and cytokines in acute lung injury. Compr Physiol 1:81-104 |
| Palchevskiy, Vyacheslav; Hashemi, Nastran; Weigt, Stephen S et al. (2011) Immune response CC chemokines CCL2 and CCL5 are associated with pulmonary sarcoidosis. Fibrogenesis Tissue Repair 4:10 |
| Weigt, S Samuel; Gregson, Aric L; Deng, Jane C et al. (2011) Respiratory viral infections in hematopoietic stem cell and solid organ transplant recipients. Semin Respir Crit Care Med 32:471-93 |
| Shahangian, Arash; Chow, Edward K; Tian, Xiaoli et al. (2009) Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice. J Clin Invest 119:1910-20 |
| Deng, Jane C; Cheng, Genhong; Newstead, Michael W et al. (2006) Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M. J Clin Invest 116:2532-42 |
