TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury

Abstract

Despite advancements in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely due to remote organ injury. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that incite a distinct pulmonary proinflammatory and proapoptotic response. Tumor necrosis factor receptor 1 (TNFR1) has been identified as a prominent death receptor activated in the lungs during ischemic AKI. We hypothesized that circulating TNF-α released from the postischemic kidney induces TNFR1-mediated pulmonary apoptosis, and we aimed to elucidate molecular pathways to programmed cell death. Using an established murine model of kidney IRI, we characterized the time course for increased circulatory and pulmonary TNF-α levels and measured concurrent upregulation of pulmonary TNFR1 expression. We then identified TNFR1-dependent pulmonary apoptosis after ischemic AKI using TNFR1-/- mice. Subsequent TNF-α signaling disruption with Etanercept implicated circulatory TNF-α as a key soluble mediator of pulmonary apoptosis and lung microvascular barrier dysfunction during ischemic AKI. We further elucidated pathways of TNFR1-mediated apoptosis with NF-κB (Complex I) and caspase-8 (Complex II) expression and discovered that TNFR1 proapoptotic signaling induces NF-κB activation. Additionally, inhibition of NF-κB (Complex I) resulted in a proapoptotic phenotype, lung barrier leak, and altered cellular flice inhibitory protein signaling independent of caspase-8 (Complex II) activation. Ischemic AKI activates soluble TNF-α and induces TNFR1-dependent pulmonary apoptosis through augmentation of the prosurvival and proapoptotic TNFR1 signaling pathway. Kidney-lung crosstalk after ischemic AKI represents a complex pathological process, yet focusing on specific biological pathways may yield potential future therapeutic targets.

Lung T Lymphocyte Trafficking and Activation during Ischemic Acute Kidney Injury

“…In our model, we found infiltration of primarily CD8 + T lymphocytes into the lungs, but both CD4 + and CD8 + T cells expressed markers of activation, suggesting that CD4 + T cells may serve an important role in crosstalk by activating cytotoxic T lymphocytes in the lungs during ischemic + T cell expression of TNFR1 or TNF-a, our prior research has identified a prominent role for the TNF superfamily in the distant organ effects of kidney IRI (8,19). In addition, we have identified TNFR1-dependent pulmonary apoptosis and increased levels of circulatory TNF-a during ischemic AKI (19). Despite no evidence of increased TNFR1 or TNF-a expression on infiltrating T cells, T nu/nu mice demonstrated significant protection from pulmonary apoptosis and functional injury during ischemic AKI.…”

“…CD8 + T cells are generally implicated in direct cytotoxicity; however, they typically require costimulation by either dendritic cells or CD4 + T cells to differentiate from naive to activated cytotoxic CD8 + T cells (30). In our model, we found infiltration of primarily CD8 + T lymphocytes into the lungs, but both CD4 + and CD8 + T cells expressed markers of activation, suggesting that CD4 + T cells may serve an important role in crosstalk by activating cytotoxic T lymphocytes in the lungs during ischemic + T cell expression of TNFR1 or TNF-a, our prior research has identified a prominent role for the TNF superfamily in the distant organ effects of kidney IRI (8,19). In addition, we have identified TNFR1-dependent pulmonary apoptosis and increased levels of circulatory TNF-a during ischemic AKI (19).…”

“…However, at 24 h, we observed greater expression of activation markers and nearly a 3-fold increase in Lung T lymphocyte TNF-a production and TNFR expression during ischemic AKI Our previous studies have suggested a prominent role for TNFR1-dependent pulmonary apoptosis following kidney IRI (8,19). To determine whether infiltrating T cells are a source for TNFdependent apoptosis, infiltrating T lymphocytes were analyzed for intracellular TNF-a and TNFR1 (CD120a) expression, using FACS analysis.…”

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

“…A likely underlying reason is the heterogeneity of the disease, which might be associated with a direct insult by, e.g., infection, aspiration, or injurious ventilation, or an indirect one during situations of severe systemic inflammation, or, frequently, a combination thereof. Efforts to define endogenous pathways or molecules that protect from ALI have recently significantly contributed to our understanding of ALI pathophysiology (5,36,51,81,95,99,132,150,176,189,226,245,254,256,261). Imai et al (106) were the first to suggest that the signals impacting on the balance between angiotensin converting enzymes (ACE) 1 and 2 modulate the degree of inflammatory lung injury after sepsis, and ACE I/D polymorphism was recently associated with mortality risk of ALI/ ARDS in patients (152).…”

Extracranial Hypothermia During Cardiac Arrest and Cardiopulmonary Resuscitation Is Neuroprotective In Vivo

“…For example, experimental acute kidney injury (AKI) causes cardiac dysfunction and induces apoptotic cell death in cardiac muscle and lungs (Hassoun et al, 2007(Hassoun et al, , 2009White et al, 2012). Similarly, both lung and bowel ischemia/reperfusion induce acute liver injury (Horie and Ishii, 2001;Esme et al, 2006).…”