Organic dust-induced lung injury and repair: Bi-directional regulation by TNFα and IL-10.

Exposure to organic dust increases chronic airway inflammatory disorders. Effective treatment strategies are lacking. It has been reported that hog barn dust extracts (HDE) induce TNFα through protein kinase C (PKC) activation and that lung inflammation is enhanced in scavenger receptor A (SRA/CD204) knockout (KO) mice following HDE. Because interleukin (IL)-10 production can limit excessive inflammation, it was hypothesized here that HDE-induced IL-10 would require CD204 to effect inflammatory responses. C57BL/6 wild-type (WT), SRA KO, and IL-10 KO mice were intranasally challenged daily for 8 days with HDE and subsequently rested for 3 days with/without recombinant IL-10 (rIL-10) treatment. Primary peritoneal macrophages (PM) and murine alveolar macrophages (MH-S cells) were treated in vitro with HDE, SRA ligand (fucoidan), rIL-10, and/or PKC isoform inhibitors. HDE induced in vivo lung IL-10 in WT, but not SRA KO mice, and similar trends were demonstrated in isolated PM from same treated mice. Lung lymphocyte aggregates and neutrophils were elevated in in vivo HDE-treated SRA and IL-10 KO mice after a 3-d recovery, and treatment during recovery with rIL-10 abrogated these responses. In vitro rIL-10 treatment reduced HDE-stimulated TNFα release in MH-S and WT PM. In SRA KO macrophages, there was reduced IL-10 and PKC zeta (ζ) activity and increased TNFα following in vitro HDE stimulation. Similarly, blocking SRA (24 hr fucoidan pre-treatment) resulted in enhanced HDE-stimulated macrophage TNFα and decreased IL-10 and PKCζ activation. PKCζ inhibitors blocked HDE-stimulated IL-10, but not TNFα. Collectively, HDE stimulates IL-10 by an SRA- and PKCζ-dependent mechanism to regulate TNFα. Enhancing resolution of dust-mediated lung inflammation through targeting IL-10 and/or SRA may represent new approaches to therapeutic interventions.

Farmer's lung disease: Analysis of 75 cases. / Enfermedad del pulmón del granjero: análisis de 75 casos.

INTRODUCTION: Farmer's lung disease (FLD) is a common form of hypersensitivity pneumonitis possibly underdiagnosed in our midst. The aim of this study was to describe clinical characteristics, evolution and factors that influence the prognosis of patients with FLD. PATIENTS AND METHODS: A retrospective study that included all patients diagnosed with FLD presenting an environmental exposure risk, a clinic, lung function and a compatible radiology, in which antigen sensitisation was demonstrated and/or a concordant pathology. RESULTS: We selected 75 patients with FLD, 50 with acute or subacute form (ASF) and 25 with chronic form (CF). Forty-four percent of patients (n=33) were diagnosed during the months of March and April, especially those with ASF compared to CF (52 vs. 28%; P=.0018). In the ASF group, DLco showed an improvement during follow-up (P=.047). The determination of specific IgG antibodies was positive in 39 patients (78%) with ASF (44% of them against Aspergillus) and CF 12 (48%). The realisation of antigenic avoidance (OR 9.26, 95% CI 1.3-66.7, P=.026) and the administration of immunosuppressive therapy (OR 16.13, 95% CI 1.26-200, P=.033) were predictors of better disease progression. CONCLUSIONS: FLD is predominantly seasonal in our environment. CF usually has a negative specific IgG antibodies unlike ASF, where antibodies against Aspergillus are the most common. The realisation of antigenic avoidance and immunosuppressive treatment are possible predictors of better disease progression.

Excellent visual outcome following Aspergillus flavus endogenous endophthalmitis-farmer's lung disease.

INTRODUCTION: The purpose is to report an eye with endogenous Aspergillus flavus endophthalmitis that achieved a good visual outcome following early and aggressive management. METHODS: A 76-year-old male recently hospitalized for allergic Aspergillus pneumonitis after cleaning out a grain bin presented with reduced vision and anterior chamber and vitreous inflammation. The patient was treated with intravenous amphotericin and a pars plana vitrectomy with intravitreal amphotericin, and the vitreous biopsy sent for histopathological and microbial analysis. RESULTS: A. flavus was isolated from the vitreous biopsy. Two weeks after vitrectomy, intravitreal amphotericin was again injected into the affected eye. The patient regained vision to 20/80 several months later, despite a moderate cataract. CONCLUSION: Early treatment of A. flavus endophthalmitis with pars plana vitrectomy, intravitreal and systemic amphotericin can lead to good visual outcomes.

[Farmer's lung cases of a farmer and his son with high BAL fluid beta-D glucan levels].

A farmer and his son, who treated straw in a cowshed, were admitted to our hospital because of severe dyspnea during summer time. Their chest X-ray films revealed bilateral reticulonodular shadows in the middle to lower lung fields. Bronchoalveolar lavage (BAL) fluid analyses showed a high proportion of lymphocytes and an increased CD4/8 ratio. They were diagnosed with farmer's lung and treated with pulse therapy with methylprednisolone and tapering of steroid. Hypoxemia and interstitial shadow improved, though the farmer relapsed one day after getting home. Immune precipitation showed positive reactions against Aspergillus fumigatus, Aspergillus terreus and Nocardiopsis alba. Their beta D-glucan levels in BAL fluid were higher than those of healthy normal volunteers, whereas their beta D-glucan levels in serum were below the detection levels. Ventilation of the cowshed and wearing a mask should prevent recurrence of the disease.

Allergic alveolitis due to herb dust exposure.

We report an episode of allergic alveolitis in a female farmer due to massive exposure to organic dust contaminated with microorganisms during threshing of herbs (thyme). The patient's medical history, the results of exposure test, inhalation challenge, and bronchoalveolar lavage suggested the diagnosis of allergic alveolitis

Antioxidant therapy partially blocks immune-induced lung fibrosis.

A mouse model of hypersensitivity pneumonitis was generated by challenge with a thermophilic actinomycete. Oxygen radical scavengers were administered to challenged mice: vitamin E at 1000 units daily, polyethylene glycol-superoxide dismutase (SOD) at 500 units daily, polyethylene glycol-catalase at 10,000 units daily, 1,3,dimethyl-2-thiourea (DMTU) at 2 mg daily, and the biomimetic SOD, copper(II) [diisopropyl salicylate]2 (CuDIPS) at 1 mg daily. At three weeks after actinomycete challenge, a 10-fold increase in bronchoalveolar (BAL) cell number was observed. Treatments with catalase or DMTU were without effect on the BAL cell number in challenged mice. However, infusion of vitamin E was associated with an increased BAL cell influx (15-fold increase at two and three weeks). Similarly, treatment with PEG-SOD and CuDIPS resulted in an increase in cell number at two and three weeks. PEG-SOD or CuDIPS treatment resulted in a strong neutrophilia, whereas control challenged mice had a cellular influx mostly of macrophages and lymphocytes. Vitamin E treatment of challenged mice led to an increased T lymphocyte recruitment at two and three weeks. In vitro studies showed that actinomycete challenge was associated with an enhancement of alveolar macrophage O2- release, which was blocked by PEG-SOD, vitamin E, or DSC treatment but was unaffected by catalase or DMTU treatment. In control challenged mice, there was a 25-fold increase in the BAL albumin concentration at two weeks. PEG-SOD, vitamin E, or CuDIPS treatment all decreased the albumin concentration; the three modulators also diminished lung fibrosis at two or three weeks, as seen by a decrease in lung hydroxyproline and collagen synthesis by lung fibroblasts. Examination of sections from lungs of challenged animals showed evidence of cellular infiltrates around the bronchi and the blood vessels. Challenged mice given continuous infusions of vitamin E, SOD, or CuDIPS had lung histological scores that were significantly lower than control challenged mice or challenged mice treated with catalase or DMTU. Thus, therapies based on O2- scavenging or treatment with a general antioxidant such as vitamin E may hold some promise in the treatment of hypersensitivity pneumonitis.

Severe farmer's lung following a workplace challenge.

A severe attack of farmer's lung developed in a dairy farmer after a workplace challenge. The patient showed full recovery after corticosteroid therapy. If a workplace challenge is considered necessary in the diagnosis of farmer's lung, care should be taken to avoid unnecessarily heavy exposure to the offending antigens.

Effect of corticosteroid treatment on the recovery of pulmonary function in farmer's lung.

The effect of corticosteroid treatment on the course of farmer's lung (FL) was studied in 36 patients randomly allocated in a double-blind placebo-controlled study. All patients were in the acute stage of the disease and had had the first diagnosed attack of FL. Twenty patients were given prednisolone treatment for 8 wk. Sixteen patients received an 8-wk placebo treatment. One patient was withdrawn from the analysis when she terminated corticosteroid treatment because of side effects. After 1 month of treatment there was a significant difference (p = 0.03) in DLCO between the treatment groups. After a follow-up of 5 yr no statistically significant differences were found between the treatment groups in FVC, FEV1, or DLCO. FL recurred in six patients during the follow-up in the corticosteroid group and in one patient in the placebo group, but the difference was not statistically significant. In conclusion, in the corticosteroid group the improvement of pulmonary function was more rapid than in the placebo group, but no influence on the long-term result was found. The possibility that corticosteroid treatment may favor the occurrence of recurrent attacks of FL needs attention.

Farmer's lung--a 5-year follow-up of eighty-six patients.

We studied the clinical course of eighty-six patients with farmer's lung for a period of 5 years. The patients were first evaluated at an acute or sub-acute stage of the disease and 1, 3, 6, 12 and 60 months thereafter. Special attention was paid to the development of lung function and radiological findings with reference to corticosteroid treatment and antigen contact during the follow-up. Many of the patients were severely ill at the acute stage of the disease. Most of the recovery took place during the first month. Significant improvement of lung function happened up to 6 months, thereafter the improvement was insignificant. After 5 years, respiratory symptoms were reported by 65% and minor respiratory dysfunction (lowered diffusing capacity) was observed in about 40% of the farmers. Thirty-two per cent of the patients showed diffuse opacities in chest X-ray. Corticosteroid treatment had no effect on long term prognosis. There was no difference in the recovery of lung function between those who returned to work compared with those who did not. Exacerbations happened in 8% of the patients during the follow-up. We conclude that respiratory symptoms, minor airway dysfunction and mild radiological fibrosis are common findings after 5 years of an acute or sub-acute stage of the farmer's lung. However, in Finland two-thirds of the patients return back to their previous occupation of farming and cattle feeding.

Severe hypoxemia in farmer's lung disease with normal findings on chest roentgenogram.

A 33-year-old woman farmer developed an acute episode of fever, cough, and shaking chills with persistent shortness of breath. Her PaO2 was 51 with a restrictive pattern on pulmonary function. Her diffusion capacity was 36 percent of predicted. In spite of these abnormalities, she always had normal chest roentgenographic findings. Further studies, including a lung biopsy, led to the diagnosis of farmer's lung disease.

Two serum markers of collagen biosynthesis as possible indicators of irreversible pulmonary impairment in farmer's lung.

Serum galactosylhydroxylysyl glucosyltransferase activity (S-GGT) and serum procollagen type III aminoterminal propeptide concentration (S-PRO(III)-N-P) were measured in 40 patients with farmer's lung at the time of an acute attack of the disease and 6 months later in order to study the usefulness of these serum markers for predicting the development of interstitial lung fibrosis. These 2 serum parameters have previously been found to reflect tissue collagen synthesis, especially in fibrotic hepatic diseases. The mean S-GGT was significantly increased when compared with the reference mean both at the time of the acute attack (p less than 0.001) and after 6 months (p less than 0.001). Approximately half of the patients had a S-GGT value higher than the upper normal limit at the acute stage, after which the levels decreased significantly (p less than 0.01). S-PRO(III)-N-P remained at the control level in most patients at the acute stage of the disease, followed by a small but significant increase (p less than 0.01), so that by the end of 6 months of follow-up one third of the patients had a S-PRO(III)-N-P value slightly above the upper normal reference value. Double blind tests on the administration of corticosteroids to half of the patients suggested that corticosteroids might have some favorable effect on the disease, although no significant response was found. The patients with definitely abnormal pulmonary function tests 1 yr after the acute stage had significantly higher initial S-GGT values than the rest of the patients (p less than 0.001). Elevated S-GGT at the acute stage was observed in 90% of the patients with definitely abnormal lung function after 1 yr but in only 30% of the other patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Farmer's lung with antibodies against Thermoactinomyces vulgaris and Aspergillus fumigatus. Clinical course and treatment]. / Pulmón de granjero con anticuerpos frente al Thermoactinomyces vulgaris y Aspergillus fumigatus. Evolución clínica y tratamiento.

We present a case of Farmer's lung with antibodies to Thermoactinomyces vulgaris and Aspergillus fumigatus. A 56-year-old male patient with an atopic family medical history came to our hospital complaining of cough, dyspnea, fever, asthenia and anorexia. His condition worsened after being exposed to cereal powder, becoming symptomatic after 20 minutes or on occasion after 6 hours. Physical examination showed basal crepitant rales in lung auscultation. The radiograph of the thorax showed a bilateral interstitial reticulo-nodular pattern. An obstructive pattern was found on functional respiratory examination. There was also a slight restriction along with the decrease of the VC and a significant reversal of the M.M.E.F. with anticholinergics. The tests for intradermal cutaneous allergies were positive after 20 minutes and for Aspergillus fumigatus Niger and Terreus (Bencard) after 6 hours. With immunoelectrophoresis and double diffusion, precipitation bands in the presence of Aspergillus fumigatus and Thermoactinomyces, were detected. IgG and IgE were high-1570 mg% and 1000 U/ml respectively. The histological study of the transbronchial biopsy showed dilatation of the alveolar septum caused by a lymphocytic infiltration with fragments of collagenous fibres. In bronchoalveolar lavage there was a predominance of lymphocytes and histiocytes. After exertion, arterial blood gases showed desaturation with hypoxemia. The static lung volumes and the flow and diffusion of carbon monoxide (CO) showed a moderate decrease of vital capacity, with the total lung capacity being below normal. Diffusion was markedly attenuated. The provocation test by indirect bronchial inhalation using cereal powder (Alfalfa) was positive. After six hours dyspnea, cough and leukocytosis appeared with an outbreak of fever and an increase in the erythrocyte sedimentation rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiologic findings in farmer's lung. Prognosis and correlation to lung function.

We classified the radiologic findings of 93 patients with acute or subacute farmer's lung (FL) disease by type and severity of the change in chest x-ray film. Acute radiologic changes, further divided as nodular, ground-glass, or striated patchy opacities, were found in 78/93 patients at the first evaluation; 11 showed chronic changes (radiologic "fibrosis"), which persisted unchanged throughout the follow-up period; and four initially had a normal chest x-ray film. Patients were followed up 23 months on an average. The more severe the radiologic change at the first evaluation, the more impaired the diffusing capacity (Dsb). Severe radiologic changes disappeared more slowly than the less severe ones. The differences in the initial pulmonary function values between the two groups disappeared during the follow-up. The type of acute change did not predict the recovery of respiratory performance. Treatment with oral corticosteroids did not affect the outcome of lung function or appearance of chronic changes, although corticosteroids seemed to hasten the disappearance of diffuse opacities. At the final evaluation, the chest x-ray film was normal in 55/93 patients. Chronic changes were detected in 38 patients. Severe radiologic appearance and striated patchy opacities predisposed to development of chronic changes.

Clinical aspects of farmer's lung: airway reactivity, treatment and prognosis.

This study reviews the results of five clinical studies dealing with farmer's lung (FL). The total number of patients included was 107, with a mean age of 49 years. All patients were farmers with dairy cattle. The clinical symptoms, auscultatory findings, chest radiography, laboratory data, partial pressure of oxygen in arterial blood at rest (PaO2), dynamic spirometry (FVC and FEV1) and lung diffusing capacity of carbon monoxide (DLco) were recorded at the first visit to the hospital and one, three, six and twelve months later during the follow-up and every six months after that. Half of the patients with FL reported insidious onset of the disease, and 28% reported acute onset. Dyspnoea was reported by all patients, coughing was almost as common. A considerable proportion of the patients reported muscle and joint pains. Diffuse opacities were detected in the chest radiograms of 99 patients (93%): the more severe the radiological change, the more impaired the DLco value. A normal chest radiogram was seen in eight of the 107 patients at the first evaluation. Half of the patients showed a restrictive type of impairment of ventilatory function at the first evaluation. Lung diffusing capacity was less than 80% of the predicted value in 89% of the patients. Ninety-nine patients were initially challenged with histamine and twenty-two of them (22%) showed increased bronchial responsiveness. Bronchial hyper-reactivity was transient in most of the patients and might also fluctuate with exacerbation of FL symptoms. Specimens of the airway epithelium of FL patients were taken by rigid bronchoscope from five patients for electronmicroscope studies. Extensive bronchial damage to the airway epithelium associated with the presence of spore-like fungi was observed. Aspiration biopsy of the spleen was carried out on ten FL patients during their first visit to the hospital. Granuloma-like reactions were detected in the aspiration biopsy material of five FL patients. The granulomatous changes in the spleen had disappeared when the procedure was repeated on two patients at an asymptomatic stage of the disease. Ninety-three patients were included in a follow-up study with a mean follow-up period of 18.6 months. The patients with clinically less severe disease were observed without medication. It appeared that corticosteroid medication was usually started if the DLco value was less than 65% of the predicted value. Fourteen patients with a DLco value less than 65% were observed without medication and served as a control group for those on medication.(ABSTRACT TRUNCATED AT 400 WORDS)