A case of non-specific interstitial pneumonia effectively treated with a combination of prednisolone and colchicine, in which granulation tissue was extensive.

A 56-year-old woman was admitted for interstitial pneumonia, and subsequently diagnosed with idiopathic non-specific interstitial pneumonia with a bronchiolitis obliterans organizing pneumonia pattern, on the basis of clinical and surgical lung biopsy findings. Histological findings revealed diffuse thickness of alveolar walls accompanied by lymphocyte infiltration and fibrosis in the lobules. In addition to those findings, granulation tissue was extensive. Although initial symptom and CT improvement occurred following high-dose prednisolone therapy, the CT did not show further improvement and her serum KL-6 level began increasing again as prednisolone was reduced. With the addition of colchicine therapy, clinical and CT findings improved remarkably and a further reduction of the prednisolone dose was achieved. This case suggests that the combination of colchicine and corticosteroids may be an effective therapy for non-specific interstitial pneumonia.

Sphingosine 1-phosphate inhibits migration and RANTES production in human bronchial smooth muscle cells.

Sphingosine 1-phosphate (S1P), a bioactive lipid mediator, has been shown to be increased in bronchoalveolar lavage fluid after allergen challenge in asthmatic patients. Here, we examined S1P actions and their intracellular signalings in cultured human bronchial smooth muscle cells (BSMCs). Expression of mRNAs of three subtypes of S1P receptors, including S1P(1), S1P(2), and S1P(3), was detected in BSMCs, and exposure of the cells to S1P inhibited platelet-derived growth factor (PDGF)-induced migration and tumor necrosis factor-alpha-induced RANTES production. S1P also inhibited PDGF-induced Rac1 activation, and dominant negative Rac1 inhibited PDGF-induced migration. On the other hand, dominant negative Galpha(q) attenuated the S1P-induced inhibition of RANTES production. Finally, an S1P(2)-selective antagonist, JTE-013, suppressed the S1P-induced inhibition of migration response and RANTES production. These results suggest that S1P attenuates cell migration by inhibiting a Rac1-dependent signaling pathway and decreases RANTES production by stimulating a Galpha(q)-dependent mechanism both possibly through the S1P(2) receptors.

8-Bromo-cAMP decreases the Ca2+ sensitivity of airway smooth muscle contraction through a mechanism distinct from inhibition of Rho-kinase.

To clarify whether cyclic AMP (cAMP)/cAMP-dependent protein kinase (PKA) activation and Rho-kinase inhibition share a common mechanism to decrease the Ca2+ sensitivity of airway smooth muscle contraction, we examined the effects of 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP), a stable cAMP analog, and (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide dihydrochloride, monohydrate (Y-27632), a Rho-kinase inhibitor, on carbachol (CCh)-, guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS)-, 4beta-phorbol 12,13-dibutyrate (PDBu)-, and leukotriene D4 (LTD4)-induced Ca2+ sensitization in alpha-toxin-permeabilized rabbit tracheal and human bronchial smooth muscle. In rabbit trachea, CCh-induced smooth muscle contraction was inhibited by 8-BrcAMP and Y-27632 to a similar extent. However, GTPgammaS-induced smooth muscle contraction was resistant to 8-BrcAMP. In the presence of a saturating concentration of Y-27632, PDBu-induced smooth muscle contraction was completely reversed by 8-BrcAMP. Conversely, PDBu-induced smooth muscle contraction was resistant to Y-27632. In the presence of a saturating concentration of 8-BrcAMP, GTPgammaS-induced Ca2+ sensitization was also reversed by Y-27632. The 8-BrcAMP had no effect on the ATP-triggered contraction of tracheal smooth muscle that had been treated with calyculin A in rigor solutions. The 8-BrcAMP and Y-27632 additively accelerated the relaxation rate of PDBu- and GTPgammaS-treated smooth muscle under myosin light chain kinase-inhibited conditions. In human bronchus, LTD4-induced smooth muscle contraction was inhibited by both 8-BrcAMP and Y-27632. We conclude that cAMP/PKA-induced Ca2+ desensitization contains at least two mechanisms: 1) inhibition of the muscarinic receptor signaling upstream from Rho activation and 2) cAMP/PKA's preferential reversal of PKC-mediated Ca2+ sensitization in airway smooth muscle.

KL-6-producing invasive thymoma.

We report a patient with KL-6-producing invasive thymoma. A 58-year-old man was admitted complaining of dyspnea and fatigability. Computed tomography of the chest revealed interstitial pneumonia and an anterior mediastinal tumor. The tumor was surgically extirpated and diagnosed as invasive thymoma. Serum KL-6 levels later increased further and another tumor was found in the liver. That liver tumor was resected and histologically diagnosed as a metastasis of thymoma. Following resection, the serum KL-6 level decreased. Tumor cells of both primary and metastatic lesions exhibited positive reactivity to immunohistochemical staining for KL-6. A review of this case is presented.

4-Hydroxy-2-nonenal enhances fibronectin production by IMR-90 human lung fibroblasts partly via activation of epidermal growth factor receptor-linked extracellular signal-regulated kinase p44/42 pathway.

To elucidate the underlying mechanisms in oxidative stress-related airway remodeling observed in chronic inflammatory pulmonary diseases such as asthma, we studied the effects of a thiol antioxidant, N-acetylcysteine (NAC), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG-1478, and tyrphostin-1 as a negative control for AG-1478 on an aldehydic product of lipid peroxidation 4-hydroxy-2-nonenal (HNE)-induced secretion of fibronectin by IMR-90 human lung fibroblasts. We also studied signal transduction pathways involved in the secretion of fibronectin evident after exposure of IMR-90 cells to HNE. Twenty-five-micromole HNE treatments of IMR-90 cells activated extracellular signal-regulated kinase p44/42 (Erk1/2) with little activation of p38 mitogen-activated protein kinase (p38MAPK) and no activation of c-Jun NH(2)-terminal kinase. HNE-induced secretion of fibronectin was inhibited by U-0126, an inhibitor of the Erk1/2 pathway, while no significant inhibition by SB-203580, an inhibitor of p38MAPK pathway, was observed. NAC and AG-1478, but not tyrphostin-1, inhibited HNE-induced fibronectin secretion accompanied by a pallarel inhibition of Erk1/2 activation. These data suggest that pulmonary oxidative stress-related lipid peroxidation may play an important role in developing airway remodeling through activating lung fibroblasts to further produce extracellular matrices, such as fibronectin, partly via activation of an EGFR-linked Erk1/2 signal transduction pathway, and that the antioxidant NAC and the EGFR tyrosine kinase inhibitor AG-1478 can be potentially useful in pulmonary diseases involving airway remodeling.

Effects of fluticasone propionate on bone mineral density in patients with persistent bronchial asthma.

OBJECTIVE: To evaluate osteoporosis in asthmatic patients. METHODS: Bone mineral density (BMD) was measured using three different methods, namely computed X-ray densitometry (CXD), digital image processing (DIP), and dual energy X-ray absorptiometry (DXA). The BMD data were standardized using the sex- and age-matched mean value of BMD. PATIENTS: One hundred and twenty-eight patients with persistent asthma. RESULTS: The standardized BMD expressed as Z-score in asthmatic patients was significantly lower than the norm (Z-score -0.48 +/- 1.17, mean +/- SD). In patients who had been continuously treated with oral corticosteroids (OCS), the standardized BMD was significantly lower than that in patients treated without OCS. In addition, the standardized BMD in patients 60 years and over (Z-score -0.71 +/- 1.10, mean +/- SD, n = 58) had decreased to a greater extent than the decrease seen in patients under 60 years (Z-score -0.30 +/- 1.21, n=70). Moreover, BMD in these older patients decreased after a 6-month treatment protocol involving the use of an inhaled corticosteroid, fluticasone propionate (FP). During the 6 months, the treatment did not affect BMD in patients who were receiving FP for the first time. Although the BMD did not decrease in patients treated with FP without OCS, the BMD in patients treated with both FP and OCS decreased during the 6 months. CONCLUSION: These results indicate that the continuous administration of OCS in patients with severe persistent asthma, particularly in older patients, may affect BMD in the short term even at a low OCS dose.

Recurrent bronchiolitis obliterans organizing pneumonia in a patient with limited cutaneous systemic sclerosis.

Systemic sclerosis (SSc) is a generalized disorder characterized by fibrosis and vascular obliteration in the skin, lung, gastrointestinal tract, and kidney. One of its two subsets is a stable, limited cutaneous group (lSSc). Pulmonary involvement in scleroderma is common, and several types of pulmonary disorders are associated with SSc. Bronchiolitis obliterans organizing pneumonia (BOOP) is a rare finding in lung disorders associated with SSc. We describe a case of lSSc with BOOP that was responsive to steroid therapy. Of interest is that the lung disorders appeared in different periods and areas. It might be important to diagnose abnormal shadows in lung fields before treatment of patients with SSc.

Interleukin-5 messenger RNA expression in peripheral blood mononuclear cells from patients with bronchial asthma and eosinophilia.

Interleukin-5 (IL-5) plays an important role in allergic diseases accompanied by eosinophilia. We examined IL-5 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMC) isolated from 13 patients with bronchial asthma, 1 patient with chronic eosinophilic pneumonia, 2 patients with idiopathic eosinophilia, and 5 control subjects. IL-5 mRNA was expressed in PBMC from 2 of 13 patients with asthma, 1 patient with chronic eosinophilic pneumonia, and 1 of 2 patients with idiopathic eosinophilia. IL-5 mRNA expression was not detected in PBMC from control subjects. PBMC from a patient with chronic eosinophilic pneumonia expressed IL-5 mRNA spontaneously. Prednisolone treatment decreased his clinical symptoms and IL-5 mRNA expression. IL-5 mRNA expression preceded revival of the disease. These observations show that IL-5 plays a role in the condition, accompanied by eosinophilia, and IL-5 mRNa examination in PBMC by means of reverse transcription-polymerase chain reaction may be useful to predict the activity of eosinophilia.