4 less injury and promote a far diminished inﬂammatory response during renal IRI. Additionally, athymic mice that subsequently underwent adoptive transfer with these TCR- restricted T cells failed to restore injury as severely as seen with transfer of wild-type T-cells [36]. T cells also play a role in long term renal modiﬁcation, as an increased number of both activated and eﬀector-memory T cells have been observed in postischemic kidneys as long as 6 weeks after IRI [37]. These T cells may in fact recognize antigens released during kidney IRI and subsequently target the kidney in an autoimmune response, leading to long-term progression of renal dysfunction. This hypothesis was demonstrated in a murine adoptive transfer model in which na¨ıve mice received T cells from mice who were 6 weeks after kidney IRI and subsequently developed albuminuria [38]. Little is known about the role of B cells in renal IRI; however, B- cell-deﬁcient mice demonstrated renal protection in the early phase of experimental IRI [39]. In summary, both the innate and adaptive immune responses play critical roles in the pathophysiology of is- chemic AKI. Either following antigen stimulation or in the presence of proinﬂammatory chemokines and oxygen free radicals, T cells undergo early activation and serve as a bridge between adaptive and innate immunity. This speciﬁc host immune response to kidney IRI facilitates distant organ crosstalk along with soluble proinﬂammatory mediators and will be further discussed in the following paragraphs. 3. Evolving Concepts of Organ Crosstalk during Ischemic AKI 3.1. Kidney-Lung Crosstalk. The combination of AKI with acute lung injury (ALI) remains a formidable challenge to clinicians caring for critically ill patients. In the setting of MOF, AKI and ALI occur more frequently together than any other combination of organ systems, and predicted mortality approaches 80% [40, 41]. This exceedingly high mortality cannot be attributed solely to volume overload; leukocyte traﬃcking, uremic toxins, and oxidative stress mechanisms all likely contribute to this devastating clinical syndrome. For the purposes of this paper, ALI represents a PaO2/FiO2 ratio <300 combined with chest radiograph ﬁndings of acute bilateral inﬁltrates in the absence of elevated cardiac ﬁlling pressures, as deﬁned by the America-European Consensus Conference on Acute Respiratory Distress Syndrome (ARDS) [42]. While the mechanisms for ischemic AKI-induced ALI remain incompletely understood, several studies point to- ward a self-propagating cycle with activation of proinﬂam- matory and proapoptotic pathways (Figure 2). AKI leads to lung injury and inﬂammation, and in turn, ALI and its atten- dant hypoxemia and hypercapnia worsened by mechanical ventilation with high positive end-expiratory pressure leads to diminishing renal hemodynamics and function. Lung injury during ischemic AKI features marked pulmonary vascular permeability, erythrocyte sludging in lung capil- laries, interstitial edema, focal alveolar hemorrhage, and inﬂammatory cell inﬁltration [12, 43, 44]. Mechanisms for International Journal of Nephrology decreased alveolar ﬂuid clearance include downregulation of pulmonary epithelial salt and water transporters including ENaC, Na, K-ATPase, and aquaporins during ischemic AKI [43–45]. This speciﬁc response likely contributes to the increased microvascular permeability and clinical pul- monary edema frequently encountered in the setting of is- chemic AKI and MOF. 3.1.1. Role of Cytokines, Chemokines, and Leukocyte Traf- ﬁcking. Experimental studies have identiﬁed a distinct pul- monary functional response and genomic signature induced during ischemic AKI which diﬀers from that induced by uremia alone. A comprehensive genomic map and ontology analysis revealed many of these top diﬀerentially expressed genes participating in proinﬂammatory and proapoptotic pathways. Genes with early and sustained activation at 6 and 36 hours after ischemic AKI included neutrophilic granule protein (Ngp), serum amyloid A3 (Saa3), and Interleukin 1- receptor type II (Il-1r2) [12]. Further investigation by Deng et al. [13] has also iden- tiﬁed an early pulmonary inﬂammatory response with rapid activation of transcription factors NF-κB and AP-1 during ischemic AKI. By 4 hours, lung expression of TNF- α and ICAM-1 led to accumulation of pulmonary neu- trophils. Leukocytes play a fundamental role in the devel- opment of ALI, and several studies have documented lung leukocyte activation and traﬃcking during experimental AKI with early and sustained neutrophil sequestration [46, 47]. Additional experiments by Klein et al. have demonstrated early expression of the neutrophil che- mokine keratinocyte-derived chemokine (KC/CXCL1) and macrophage inﬂammatory protein (MIP-2/CXCL-2) along with increased pulmonary myeloperoxidase activity and pulmonary microvascular permeability during ischemic AKI [45]. The authors also examined interleukin-6, a neutrophil- recruiting chemokine previously identiﬁed as a candidate gene by preferential expression in whole lung tissue during ischemic AKI [48], and determined it was critical for inﬂu- encing lymphocyte traﬃcking and pulmonary permeability [45]. While neutrophils are key mediators in several extra- pulmonary models of ALI such as sepsis and mesenteric IRI, their role in ischemic AKI-induced ALI remains to be elucidated. Uremic neutrophils have even demonstrated a protective eﬀect in the setting of ALI [49]. Clearly, leukocyte traﬃcking and the innate immune response play a complex and important role in mediating the pulmonary inﬂamma- tory response and dysfunction during renal IRI. 3.1.2. Lung Apoptosis. Though not traditionally associated with a proinﬂammatory response, pulmonary apoptosis plays a critical role in the genomic and phenotypic response to ischemic AKI. Apoptosis of pulmonary epithelial and endothelial cells along with delayed leukocyte apoptosis occurs during ALI [50–52]. Pulmonary apoptosis dis- rupts tethering forces involved in cell-to-cell and cell-to- extracellular matrix interactions, leading to a loss of endothe- lial barrier function and increased vascular permeability