Acute pancreatitis in juvenile systemic lupus erythematosus: a manifestation of macrophage activation syndrome?

Acute pancreatitis (AP) is a rare and life-threatening manifestation of juvenile systemic lupus erythematosus (JSLE). The objective of this study was to evaluate the prevalence and clinical features of AP in our JSLE population. AP was defined according to the presence of abdominal pain or vomiting associated to an increase of pancreatic enzymes and/or pancreatic radiological abnormalities. Of note, in the last 26 years, 5367 patients were followed up at our Pediatric Rheumatology Unit and 263 (4.9%) of them had JSLE diagnosis (ACR criteria). AP was observed in 4.2% (11/263) of JSLE patients. The median of age of the JSLE patients at AP diagnosis was 12.4 years (8.8-17.9). All of them had lupus disease activity at AP onset. Three patients were receiving corticosteroids before AP diagnosis. Interestingly, 10/11 JSLE patients fulfilled preliminary guidelines for macrophage activation syndrome, three of them with macrophage hemophagocytosis in bone marrow aspirate and hyperferritinemia. The hallmark of this syndrome is excessive activation and proliferation of T lymphocytes and macrophages with massive hypersecretion of proinflammatory cytokines and clinically it is characterized by the occurrence of unexplained fever, cytopenia and hyperferritinemia. AP treatment was mainly based on intravenous methylprednisolone. Four JSLE patients with AP died and two developed diabetes mellitus. In conclusion, AP was a rare and severe manifestation in active pediatric lupus. The association between AP and macrophage activation syndrome suggests that the pancreas could be a target organ of this syndrome and that pancreatic enzyme evaluation should also be carried out in all patients.

[Relapse of small cell carcinoma of the lung with metastasis to iris].

We reported a case of small cell carcinoma of the lung with metastasis to the iris during a stage of complete remission obtained with chemotherapy and radiation therapy. The patient was a 55-year-old man hospitalized for hoarseness and abnormal chest radiographs in August 1996. Small cell carcinoma of the lung had been diagnosed, and the stage was limited disease. Treatment consisted of 3 cycles of chemotherapy with cisplatin and etoposide, together with radiation therapy. The patient achieved complete remission and was discharged. In mid-December, he visited an eye clinic with the complaints of blurred vision and congestion in the right eye. Metastatic tumor of the iris was diagnosed. At that time, neither local recurrence of the lung cancer nor metastasis to other organs were observed. The patient was treated with cisplatin and etoposide again, resulting in a reduction of the iris tumor's size. After chemotherapy, the right eye was treated with electron irradiation, and the iris tumor and other clinical signs almost entirely disappeared. The patient retained normal vision during the clinical course.

[Sarcoidosis differentially diagnosed from mediastinal tumor by thoracoscopic biopsy].

A 46-year-old man presented with swallowing difficulty and dyspnea when in the supine position. Chest X-ray and computed tomographic (CT) films disclosed left pleural effusion and a tumor shadow extending invasively from superior to anterior mediastinum around the heart and large arteries. These observations called for a differential diagnosis from malignant lymphoma, invasive thymoma, and small cell carcinoma. Bronchofiberscopy and percutaneous tumor biopsy were performed, but the findings were inconclusive. Thoracoscopic biopsy yielded a diagnosis of sarcoidosis. No extrathoracic lesions were detected. Corticosteroid therapy (30 mg/day of prednisolone) was started. After 6 months of treatment (7.5 mg/day of prednisolone), the tumor shadow was reduced in size and the patient's swallowing difficulty and dyspnea subsided. This was a rare case of sarcoidosis extending invasively around the heart and large arteries, and that needed to be differentiated from mediastinal tumor. Thoracoscopic biopsy should be actively enlisted as a diagnostic procedure in difficult cases of this kind.

Hyperventilation-induced airway injury and vascular leakage in dogs: effects of alpha1-adrenergic agonists.

alpha1-Adrenergic agonists inhibit hyperventilation-induced bronchoconstriction (HIB) in dogs. We tested the hypothesis that alpha-agonists inhibit HIB by reducing bronchovascular leakage and edema that theoretically could cause airway obstruction. Peripheral airways were isolated by using a bronchoscope; pretreated with either methoxamine (Mx), norepinephrine (NE), or saline aerosol; and then exposed to a 2,000 ml/min dry-air challenge (DAC) for 2 min. Colloidal carbon was injected before DAC and used to quantify bronchovascular permeability. Mx-, NE-, and vehicle-treated airways were prepared for morphometric analysis within 1 h after DAC. Light microscopy revealed that the 2-min DAC produced minimal bronchovascular leakage and little epithelial damage. However, pretreatment with either Mx or NE significantly enhanced dry air-induced bronchovascular hyperpermeability and mucosal injury. The increased damage associated with these alpha1-agonists implicates a protective role for the bronchial circulation. The fact that alpha1-agonists inhibit HIB suggests that neither dry air-induced leakage nor injury directly contributes to the development of airway obstruction. In addition, our data suggest that alpha-agonists attenuate HIB in part by augmenting hyperventilation-induced bronchovascular leakage and by replacing airway water lost during a DAC.

Effect of furosemide on hyperpnea-induced airway obstruction, injury, and microvascular leakage.

Furosemide attenuates hyperpnea-induced airway obstruction (HIAO) in asthmatic subjects via unknown mechanism(s). We studied the effect of furosemide on dry air-induced bronchoconstriction, mucosal injury, and bronchovascular hyperpermeability in a canine model of exercise-induced asthma. Peripheral airway resistance (Rp) was recorded before and after a 2-min dry-air challenge (DAC) at 2,000 ml/min. After pretreatment with aerosolized saline containing 0.75% dimethyl sulfoxide, DAC increased Rp 72 +/- 11% (SE, n = 7) above baseline; aerosolized furosemide (10(-3) M) reduced this response by approximately 50 +/- 6% (P < 0.01). To assess bronchovascular permeability, colloidal carbon was injected (1 ml/kg i.v.) 1 min before DAC, and after 1 h, the vehicle- and furosemide-treated airways were prepared for morphometric analysis. Light microscopy confirmed previous studies showing that DAC damaged the airway epithelium and enhanced bronchovascular permeability. Furosemide did not inhibit dry air-induced mucosal injury or bronchovascular hyperpermeability and in fact tended to increase airway damage and vascular leakage. This positive trend toward enhanced bronchovascular permeability in DAC canine peripheral airways is consistent with the hypothesis that furosemide inhibits HIAO in part by enhancing microvascular leakage and thus counterbalancing the evaporative water loss that occurs during hyperpnea.

Eicosanoids modulate hyperpnea-induced bronchoconstriction in canine peripheral airways.

We examined the role of leukotrienes (LTs) in the development of dry air-induced bronchoconstriction (AIB) in canine peripheral airways. Airway reactivity to exogenous LTs was first tested by using an LTD4 aerosol challenge: peripheral airway resistance increased approximately 130 +/- 51% (n = 4) above baseline when compared with its vehicle control. AIB was then assessed by measuring peripheral airway resistance after, and airway wall temperature during, a dry air challenge (DAC). Treatment with a peptidoleukotriene biosynthesis inhibitor (MK-0591) attenuated AIB by approximately 65% without altering airway wall temperature. The fact that MK-0591 did not alter airway reactivity to aerosolized acetylcholine and completely inhibited Ca2+ ionophore-induced LTB4 generation in canine whole blood attests to the specificity of the drug. Treatment with MK-0591 did not affect the increased number of epithelial cells recovered in bronchoalveolar lavage fluid 5 min after DAC. Concentrations of LTs and other eicosanoids in bronchoalveolar lavage fluid from vehicle-treated DAC airways were increased above baseline values; only LTs were reduced by MK-0591. Before MK-0591, AIB was significantly correlated with the dry air-induced generation of LTC4, LTD4, and LTE4. After treatment with MK-0591, AIB was correlated with thromboxane B2, prostaglandin (PG) F2 alpha, and PGE2. We conclude that hyperpnea with dry air stimulates local production and release of LTs in canine bronchi and, alone with the generation of bronchoconstricting and bronchodilating PGs, plays a central role in the modulation of AIB.

The effect of bronchial blood flow on hyperpnea-induced airway obstruction and injury.

We examined the effect of bronchial blood flow (BBF) on hyperpnea-induced airway obstruction (HIAO) in dogs. HIAO in in situ isolated pulmonary lobes with or without BBF was monitored via a bronchoscope. An intravascular tracer in conjunction with morphometric analysis was used to document the efficacy of our occlusion technique. We found that (a) Occlusion of the bronchial artery abolished bronchovascular leakage, but did not alter HIAO; (b) HIAO occurred in postmortem dogs, and was attenuated by cooling; (c) absence of BBF did not cause mucosal damage, although hyperpnea-induced injury was enhanced in airways lacking BBF; (d) BBF did not affect either goblet/ ciliated cell ratios or hyperpnea-induced goblet cell degranulation; (e) ligation of the bronchial artery and hyperpnea each caused mast cell degranulation, and these effects were additive; (f) hyperpnea-induced leukocyte infiltration was reduced in the absence of BBF; and (g) ligation of the bronchial artery and hyperpnea with dry air each increased airway vessel diameter, and these effects were additive. We conclude that either impairment or absence of BBF abolishes bronchovascular leakage and increases hyperpnea-induced mucosal injury, but fails to affect HIAO. Based on these results we speculate that bronchovascular leakage protects the bronchial mucosa from excessive losses of heat and water, and inhibits mucosal damage.

The effects of alpha-adrenergic agonists on hyperpnea-induced airway obstruction in dogs.

Two alpha-adrenergic agonists that inhibit hyperpnea-induced airway obstruction (HIAO) in asthmatic subjects were used to examine the role of bronchial blood flow in the development of HIAO in canine periphery airways. A bronchoscope was used to record peripheral airway resistance (Rp) in anesthetized dogs before and after hyperpnea with dry air. Hyperpnea increased Rp 64 +/- 8% (mean +/- SE) above baseline. Treatment with norepinephrine (NOR) either before or at various times after hyperpnea inhibited HIAO (p < 0.01). We also found that NOR inhibited acetylcholine-induced bronchoconstriction. However, beta-adrenergic blockade with propranolol completely eliminated these effects. Thus, NOR inhibited HIAO in canine peripheral airways via the stimulation of beta-adrenergic receptors and the attenuation of airway smooth muscle contractility. In contrast, pretreatment with methoxamine (MX) decreased HIAO by approximately 25% when compared with the vehicle control, and this effect was completely eliminated by alpha-adrenergic blockade with phentolamine. Relative to NOR, MX provides weak protection against HIAO via the direct stimulation of alpha-adrenergic receptors and their subsequent effect on either mucus secretion or bronchovascular tone. We conclude that bronchial blood flow plays at best a minor role in the development of HIAO.

A beta 2-adrenergic agonist inhibits dry air-induced injury in canine peripheral airways.

We examined the effects of a beta 2-agonist on dry air-induced injury in canine peripheral airways. Dry air-induced bronchoconstriction (AIB) was assessed by measuring peripheral airway resistance in anesthetized dogs. Salbutamol reduced AIB by approximately 75% compared with control values. Colloidal carbon was used to detect bronchovascular leakage in contralateral sublobar segments that were pretreated with saline or salbutamol. About 87% of the perimeter of bronchi was damaged after dry air challenge in saline-treated segments. Salbutamol reduced mucosal damage by approximately 30% (P < 0.05). The mucosa of bronchioles was not injured. The average goblet-to-ciliated cell ratio (which reflects mucosal perturbation) in bronchi decreased from 0.38 in control bronchi to 0.15 in challenged bronchi, and this effect was also evident in bronchioles. Salbutamol did not affect this decrement. Dry air challenge also caused degranulation of mast cells located below damaged mucosa, dilation of bronchial vessels, and leakage from capillaries and venules located below normal ciliated and damaged mucosa of bronchi. Thus, we conclude that salbutamol attenuates epithelial damage and AIB but fails to inhibit mast cell degranulation and vascular hyperpermeability.

Hyperpnea with dry air causes time-dependent alterations in mucosal morphology and bronchovascular permeability.

This study examines the morphological and physiological changes that occur in canine peripheral airways after hyperpnea with dry air. Peripheral airways were exposed to a 5-min 2,000 ml/min dry air challenge (DAC) at 24, 6, 2, or 1 h before or 60 s after (0 h) the injection of colloidal carbon. After recording the dry air-induced increase in peripheral airway resistance, the lungs were removed and prepared for morphometric analysis (n = 5). Light microscopy revealed that 50% of the airway perimeter appeared damaged at 0, 1, and 2 h after DAC, and repair was evident 6-24 h after the challenge. The average goblet-to-ciliated cell ratio decreased from 0.34 before DAC to 0.15 after DAC and recovered within 24 h. Dry air-induced bronchovascular leakage occurred immediately after DAC and persisted for > or = 24 h. DAC decreased mast cell number only in regions where the mucosa was damaged, and this decrease was inversely correlated with bronchovascular leakage. Finally, leukocyte infiltration was evident 1-2 h after DAC and continued throughout the 24-h period. We conclude that hyperpnea with dry air causes mucosal injury, inflammation, and microvascular leakage and that these dry air-induced effects persist for > or = 24 h after DAC.

Dry air-induced mucosal cell injury and bronchovascular leakage in canine peripheral airways.

The purpose of this study was to examine the relationship between hyperpnea-induced mucosal injury, bronchovascular hyperpermeability, and airway reactivity. Hyperpnea-induced bronchoconstriction was assessed by measuring peripheral airway resistance (Rp) in anesthetized mechanically ventilated male mongrel dogs. Either colloidal carbon or monastral blue was used to localize bronchovascular leakage after a 5-min exposure to either a 1000 ml/min dry, 2000 ml/min wet, or 2000 ml/min dry air challenge. Morphometric analyses of cross-sectioned bronchi revealed that hyperpnea with dry air stimulated goblet cell degranulation, damaged the bronchial mucosa, and increased bronchovascular permeability. Exposure to only a 2000 ml/min dry air challenge produced marked mucosal injury when compared with control. Regardless of treatment, bronchial vessels lying below normal mucosa characterized by goblet/ciliated cell (G/C) ratios > or = 0.3 did not leak. A G/C transition zone between 0 and 0.3 separated normal from damaged mucosa. Within this zone, vascular permeability was inversely correlated with G/C ratio. In addition, airflow-induced changes in Rp were inversely related to G/C ratio and positively correlated with bronchovascular leakage. Although these correlations are consistent with the speculation that bronchovascular leakage and edema formation are responsible for the dry air-induced changes in Rp, it is equally plausible that bronchovascular leakage is not the cause of but occurs in concert with airway narrowing to protect cells in the bronchial mucosa from excessive losses of heat and water.

Dry air- and hypertonic aerosol-induced bronchoconstriction and cellular responses in the canine lung periphery.

Dry air and hypertonic saline both create an osmotic stress to the airways, whilst dry air alone induces transient cooling of the airway mucosa. It is unclear whether these two stimuli lead to bronchoconstriction via the same mechanisms. We compared airflow- and hypertonic aerosol-induced bronchoconstriction (AIB and HIB, respectively) in the canine lung periphery, using a wedged bronchoscope to measure collateral system resistance (Rcs). Bronchoalveolar lavage (BAL) was used to examine changes in cells and mediators during AIB and HIB. We found that: 1) peripheral airways are not refractory to either dry air or hypertonic aerosols, and do not exhibit cross-refractoriness to these stimuli; 2) differences in strength of stimulus can alter the magnitude but not the time course of HIB; 3) within an individual, AIB and HIB are significantly correlated; 4) epithelial cells recovered in BAL fluid (BALF) are significantly elevated after AIB, and are similarly increased after HIB; 5) when compared to control, mediators recovered in BALF are significantly elevated after AIB but not HIB; 6) HIB is not altered by cyclo-oxygenase inhibition; and 7) lavage with hypertonic fluid does not affect the number of epithelial cells recovered, although the concentrations of some mediators are increased. We speculate that differences in cell and mediator profiles reflect differences in the time course of AIB and HIB that result from the modulation of temperature sensitive pathways that occurs during dry air, but not during hypertonic aerosol challenge.