Hamid Rabb

Prominent and sustained up-regulation of gp130-signaling cytokines and the chemokine MIP-2 in murine renal ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) is a major cause of renal dysfunction in both native kidneys and renal allografts. To broaden our understanding of the inflammatory mediators involved in IRI, we used multi-probe RNase protection assays to examine the expression of 26 different cytokine genes in a murine model of renal IRI. We observed that, in addition to up-regulation of IL-1beta and to a lesser extent TNF-alpha, IRI was associated with an intense and sustained up-regulation of three gp130-signaling cytokines, IL-6, IL-11, and leukemia inhibitory factor (LIF), as well as with up-regulation of the neutrophil chemotactic and activating mediator macrophage inflammatory protein (MIP)-2. Macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein (MCP)-1 were also moderately up-regulated after IRI, whereas mRNA levels of several other inflammatory mediators including IL-1alpha, IL-2, IL-4, interferon (IFN)-gamma, GM-CSF, and RANTES were minimally increased or remained undetectable. These findings identify MIP-2 as an attractive target for inhibition of leukocyte recruitment in renal IRI and also suggest a potentially novel role for gp130-mediated signals in IRI.

Recurrent Respiratory Syncytial Virus Infections in Allergen-Sensitized Mice Lead to Persistent Airway Inflammation and Hyperresponsiveness

Respiratory syncytial virus (RSV) infection is considered a risk factor for bronchial asthma; however, the synergy between allergen sensitization and RSV infection in the development of pulmonary inflammation and asthma has been controversial. In this study the effects of primary and recurrent RSV infection on allergic asthma were examined in a group of control, RSV-infected, Dermatophagoides farinae (Df) allergen-sensitized, and Df allergen-sensitized plus RSV-infected BALB/c mice. Primary RSV infection in Df-sensitized mice transiently increases airway responsiveness, which is accompanied by increases in eosinophilic infiltration, the expression of ICAM-1, and macrophage inflammatory protein-1α (MIP-1α) in the lung tissue. A secondary RSV infection persistently enhances airway responsiveness in Df-sensitized mice, with a concomitant increase in MIP-1α and RSV Ag load in lung tissues. Bulk cultures of thoracic lymph node mononuclear cells demonstrate that acute RSV infection augments both Th1- and Th2-like cytokines, whereas secondary and tertiary infections shift the cytokine profile in favor of the Th2-like cytokine response in Df-sensitized mice. The elevated total serum IgE level in the Df-sensitized mice persists following only RSV reinfection. Thus, recurrent RSV infections in Df-sensitized mice augment the synthesis of Th2-like cytokines, total serum IgE Abs, and MIP-1α, which are responsible for persistent airway inflammation and hyperresponsiveness, both of which are characteristics of asthma.

Genetic susceptibility to renal ischemia reperfusion injury revealed in a murine model

BACKGROUNDnThe development of genetically engineered mice has led to increased use of mouse models to study renal ischemic reperfusion injury (IRI). We hypothesized that susceptibility to IRI could result from strain differences due to genetic factors.nnnMETHODSnOur study compared recovery subsequent to renal IRI in NIH Swiss, C57BL/6, and BALB/c mice. Serum creatinine (SCr) and blood urea nitrogen (BUN) levels were evaluated postischemia. We also conducted reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of renal cytokines and adhesion molecules postischemia.nnnRESULTSnAt 48 hr postischemia, renal dysfunction in NIH Swiss mice was significantly reduced, compared with other groups (P<0.01). BUN measurements confirmed renal protection at 48 hr in the NIH Swiss group. RT-PCR analysis of mRNA postischemia demonstrated that, between strains, there was little difference in mRNA expression for renal cytokines and adhesion molecules.nnnCONCLUSIONSnNIH Swiss mice appear to be resistant in susceptibility to renal IRI. Early expression of pro-inflammatory genes was not associated with resistance to IRI, thus genetic factors could be important in outcome after renal IRI.

Evaluation of urinary markers in acute renal failure.

Acute renal failure continues to be a difficult clinical problem despite developments in dialysis and critical care. Diagnosis of the etiology frequently determines treatment. Urinalysis remains an essential diagnostic tool in the approach to acute renal failure, particularly with the current emphasis on cost-containment and evidence-based medicine. This review focuses on some of the characteristic features in the urinalysis found in different forms of acute renal failure, current developments into the molecular basis for these urinary abnormalities, and new markers on the horizon.

Possible molecular basis for changes in potassium handling in acute renal failure

Renal potassium excretion is diminished in acute renal failure (ARF). The gastrointestinal tract can compensate for deficient renal potassium excretion in many patients with ARF. For both impaired renal potassium excretion and gastrointestinal compensation in ARF, little is known about the role of potassium channels. We hypothesized that specific changes in the expression of the secretory renal outer medullary potassium channel (ROMK), and the potassium channel regulator, channel-inducing factor (CHIF), in kidney and colon could contribute to changes in potassium handling. Sprague-Dawley rats underwent uninephrectomy and 35 minutes of renal ischemia, followed by varying periods of reperfusion. Renal function, serum and urine potassium levels, and aldosterone levels were measured. The expression of messenger RNA (mRNA) for ROMK and CHIF in the kidney and CHIF in the colon were measured by Northern blot hybridization. Serum creatinine level was increased at 24 hours and started to decline at 48 hours of renal ischemia reperfusion injury (IRI). Serum potassium level was increased at 24 hours, further elevated at 48 hours of IRI, and returned to normal at 7 days of IRI. Urine potassium level was reduced at 24 and 48 hours. Northern blot analysis indicated that the expression of ROMK1 mRNA in the cortex or medulla remained unchanged at 24 hours but profoundly decreased (by 70% to 80%) at 48 hours (n = 4; P < 0.01). The expression of CHIF mRNA in the kidney cortex or medulla decreased by 25% to 30% at 24 hours and 35% to 40% at 48 hours of IRI (n = 4; P < 0.05 for each group). CHIF mRNA expression in the distal colon was moderately increased at 24 hours (approximately twofold) and significantly enhanced at 48 hours (more than threefold; P < 0.01; n = 4) of IRI. Serum aldosterone level was increased approximately threefold at 48 hours of IRI (P < 0.01; n = 6). In conclusion, (1) suppression of ROMK and CHIF in the kidney may contribute to decreased renal potassium excretion in ARF; (2) enhanced expression of CHIF in the distal colon in IRI could be an adaptive response to increase potassium excretion in the colon and help modify hyperkalemia in ARF; and (3) increased aldosterone levels, as a response to hyperkalemia, could be upregulating colonic CHIF.

Leukocyte adhesion molecules in transplantation

Dramatic developments in organ transplantation have revolutionized the care of the patient with a failing organ. Despite these advances, however, acute and chronic rejection remain important clinical problems. As reflected by the contributions in this series, in the past decade there have been great advances in our knowledge of characteristics of cellular adhesion molecules and the contributions of those molecules to disease processes. The ground work has been laid for a better understanding of the mechanisms involved in allograft rejection, detection of early rejection, and development of therapies that will extend graft survival and improve the care of the transplant patient. We will review some of the roles played by adhesion molecules in pathophysiology, diagnosis, and treatment in organ transplantation. At the present time, the organ most commonly transplanted is the kidney. Thus, kidney transplantation will be the focus for much of the discussion. Because of the pivotal role of the leukocyte in the immune response to transplantation, we will limit this review to the leukocyte‐ endothelial adhesion molecules (LAMs). Because of space limitations, this review cannot be exhaustive and will, by necessity, leave out important contributions. Previous articles in this series have extensively reviewed the structure and functions of cell adhesion molecules in select diseases. Because of the rapid changes in this field as well as for the benefit of the uninitiated reader, we will briefly summarize the basic biology and terminology used for the major LAMs.