A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.

TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection.

BACKGROUND: Rhinoviruses (RV) are the most common acute triggers of asthma, and airway epithelial cells are the primary site of infection. Asthmatic bronchial epithelial cells (BECs) have been found to have impaired innate immune responses to RV. RV entry and replication is recognized by pathogen recognition receptors (PRRs), specifically toll-like receptor (TLR)3 and the RNA helicases; retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). OBJECTIVE: Our aim was to assess the relative importance of these PRRs in primary bronchial epithelial cells (pBEC) from healthy controls and asthmatics following RV infection and determine whether deficient innate immune responses in asthmatic pBECs were due to abnormal signalling via these PRRs. METHODS: The expression patterns and roles of TLR3 and MDA5 were investigated using siRNA knock-down, with subsequent RV1B infection in pBECs from each patient group. We also used BX795, a specific inhibitor of TBK1 and IKKi. RESULTS: Asthmatic pBECs had significantly reduced release of IL-6, CXCL-8 and IFN-λ in response to RV1B infection compared with healthy pBECs. In healthy pBECs, siMDA5, siTLR3 and BX795 all reduced release of IL-6, CXCL-10 and IFN-λ to infection. In contrast, in asthmatic pBECs where responses were already reduced, there was no further reduction in IL-6 and IFN-λ, although there was in CXCL-10. CONCLUSION AND CLINICAL RELEVANCE: Impaired antiviral responses in asthmatic pBECs are not due to deficient expression of PRRs; MDA5 and TLR3, but an inability to later activate types I and III interferon immune responses to RV infection, potentially increasing susceptibility to the effects of RV infection.

Accuracy of 1H and 31P MRS analyses of lactate in skeletal muscle.

As the end product of anaerobic metabolism and a source of H(+), lactic acid is important in metabolism and pH regulation. Several methods have been introduced to calculate changes in the lactate anion (Lac(-)) concentration in exercising skeletal muscle from information derived from the (31)P spectrum. Alternatively, Lac-may be observed directly with (1)H MRS. Both (1)H and (31)P spectroscopy have potential problems, which could prevent accurate determination of [Lac(-)]. It is demonstrated that quantitatively accurate (1)H MRS measurements of changes in [Lac(-)] due to exercise are possible in isolated muscle. In general, calculation by (31)P MRS overestimates Lac-production. An analysis is presented of possible sources of errors in the (1)H and (31)P MRS methods.

Offset-dependent partial saturation in binomial solvent suppression sequences.

In vivo spectroscopic experiments are commonly done under partially T1 saturated conditions and saturation factors (observed signal intensity divided by fully relaxed intensity) used for quantitative analysis of absolute and relative metabolite concentrations. The conventional calculation of the saturation factor assumes uniform excitation across the spectrum. This assumption is violated when selective-excitation solvent peak suppression techniques, such as binomial sequences, are used. In this case, the degree of partial saturation, and hence the saturation factor, is dependent on the resonance offset. This has implications for the frequency offset of maximum excitation, solvent suppression effectiveness, absolute and relative quantitative measurements, and progressive saturation T1 measurements. In this paper, the jump and return (JR) and jump and return echo (JRE) sequences are examined in detail with regard to these implications. It is shown that offset-dependent partial saturation depends on the sequence used and can become significant. A saturation factor which is a function of offset can be used to correct for this effect and allow for proper quantitative interpretation of experimental results under partially saturated conditions.

Renal osteodystrophy in children with chronic renal failure: an unexpectedly common and incapactating complication.

The incidence, age at onset, and progression of the biochemical, radiographic, and histologic characteristics of renal osteodystrophy were studied in 50 children in whom chronic renal failure had been recently diagnosed. During a ten-year observation period, 19 patients progressed to end-stage renal failure and radiographic signs of renal osteodystrophy developed in 15 of these (79%). Renal osteodystrophy developed in all nine patients whose chronic renal failure was diagnosed before 3 years of age and in six of the ten children with later onset of failure. The mean interval from diagnosis of renal failure to development of osteodystrophy was 1.4 years. Radiographically, growth zone lesions predominated in the younger children, whereas cortical erosions were more prevalent in the older children. Histologic examination, performed in 38 patients, showed both defective mineralization and excessive resorption and was a more sensitive diagnostic index than radiography. Noticeable deformities developed in one third of the patients with osteodystrophy, despite medical treatment including vitamin D2 therapy. Deformities were particularly frequent and severe in patients whose renal failure developed in infancy. In all 13 patients whose growth patterns were studied before and after osteodystrophy developed, the onset of bone lesions was associated with a deterioration of growth, indicating that osteodystrophy plays a major role in causing the growth retardation commonly observed in children with chronic renal failure.

Gonadal function in males treated with cyclophosphamide for nephrotic syndrome.

Analysis of semen from 16 patients treated with cyclophosphamide for nephrotic syndrome showed azoospermia in three and oligospermia in seven. Analysis was normal in the other six. Prolonged treatment, particularly with larger total dosage, was associated with a higher incidence of gonadal dysfunction. Recovery was not evident at follow-up, 2 years and 9 months to 9 years and 1 month after cessation of the therapy. Limitation of treatment with cyclophosphamide to 8 weeks/course (2.5 mg/kg/day) minimizes this side effect without greatly increasing the rate of relapse of the nephrotic syndrome in the first 2 years after therapy.

Allograft renal-artery stenosis: increased peripheral plasma renin activity as an early indicator of uncontrollable hypertension.

We measured indices of the renin-aldosterone system and body-fluid spaces in 11 adolescents who had received a renal transplant after removal of their own diseased kidneys. None had hypervolemia but 6 had hypertension. Renal angiography revealed greater than 50% luminal occlusion by allograft renal-artery stenosis (RAS) in only the 3 patients who had severe hypertension refractory to conventional medical therapy. Excessive peripheral plasma renin activity (PRA) distinguished these patients from those who had less severe stenosis or normal angiogram, and diuretic stimulation heightened the PRA differences. We conclude that significant allograft RAS does not necessarily act like a typical single-kidney Goldblatt model until after volume depletion. Our findings indicate that peripheral PRA values can be used to assess the degree of graft ischemia clinically. This permits early identification of patients who have severe RAS that probably will be difficult to control medically, and, therefore, should be followed closely with a view of reconstructive vascular surgery before further deterioration of renal function.

Renal allograft biopsy: a satisfactory adjunct for predicting renal function after graft rejection.

Forty-four biopsies of transplanted kidneys undergoing rejection were examined by light microscopy without knowledge of the eventual clinical outcome. All patients received extensive antirejection medication. A scoring system based on nine histopathologic criteria was formulated to predict whether the serum creatinine would be less than 1.8 mg/dl (good prognosis), 1.8 to 2.5 mg/dl (fair), or greater than 2.5 mg/dl (poor), two months after biopsy. Predictions were accurate in 37 of the 44 cases. In some cases with relatively minimal vascular changes the prognosis was poor, whereas heavy cellular infiltreate without vessel damage did not necessarily preclude functional recovery. It was concluded that specific histopathologic pictures should enable the physician to decide whether to institute extensive antirejection therapy or adopt alternative measures.

Effect of chronic renal failure, dialysis and transplantation on motor nerve conduction velocity in children.

Ulnar and peroneal motor nerve conduction volocities (MNCVs) were measured in 47 children in a dialysis-transplantation program. Mean peroneal MNCV was significantly decreased from normal in children with mild renal failure (serum creatinine concentration, 1.5 to 2.9 mg/dl), whereas ulnar MNCV was significantly decreased only when the serum creatinine value was at least 9 mg/dl. Both ulnar and peroneal MNCVs remained unchanged during long-term hemodialysis or peritoneal dialysis; however, after individual dialyses ulnar MNCV increased. After renal transplantation ulnar MNCV returned to normal within a year and peroneal MNCV within 3 years. Before dialysis was required and during long-term dialysis most plasma magnesium values were elevated; ionized calcium activity was decreased in about 50% of determinations. After transplantation and the concentration of divalent cations rapidly returned to normal. These children differed from adults studied in that (a) there was no correlation between severity of renal failure and MNCV, (b) long-term dialysis did not improve MNCV and (c) peroneal velocities did not recover for 3 years after transplantation.