The effect of recombinant sTGFß1RII and sIL13Rα2 receptor proteins on schistosomiasis japonica, hepatic fibrosis and signal transduction in a mouse model of schistosome disease.

This study was designed to investigate the effect of recombinant sTGFß1RII and sIL13Rα2 receptor proteins on schistosomiasis japonica, hepatic fibrosis and the expression of SMAD3 and STAT6. The proteins sTGFß1RII and sIL13Rα2 were expressed in Escherichiacoli, purified using affinity chromatography and characterized by Western blotting. Female BALB/C mice (48) were randomly divided into eight groups and infected with Schistosoma japonicum. Five weeks after infection, test groups were injected with the recombinant proteins at different doses. Eight weeks after infection, lung and hepatic tissue samples were obtained and stained with hematoxylin and eosin (HE) and Masson's trichrome. Immunohistochemical staining was used to detect the expression of SMAD3 and STAT6. The recombinant proteins sTGFß1RII and sIL13Rα2 were successfully expressed, purified, and characterized. The granuloma area, hepatic hydroxyproline (HYP) level and hepatic fibrosis of the protein therapeutic groups were significantly smaller than those of the positive control group (P<0.01). Treatment with sTGFß1RII was more effective when the protein was administered for 4weeks rather than 2 (P<0.01). Hepatic fibrosis in the groups using a low dose of protein sTGFß1 was lower that of the combination group (P<0.05). The expression level of STAT6 was significantly lower in groups treated with sIL13Rα2 than in groups not treated with the protein (P<0.01). The recombinant proteins TGFß1RII and sIL13Rα2 were able to decrease granuloma area and hepatic fibrosis in schistosomiasis japonica, and also reduced the expression of the signal transduction proteins SMAD3 and STAT6. The proteins were more effective when used in combination than when applied singly.

Lung histopathology, radiography, high-resolution computed tomography, and bronchio-alveolar lavage cytology are altered by Toxocara cati infection in cats and is independent of development of adult intestinal parasites.

This study presents clinical findings after oral ingestion of Toxocara cati eggs which resulted in rapid pulmonary lung migration and parenchymal disease, noted on clinically relevant diagnostic methods. Further, the study investigated the efficacy of pre-infection applications of preventative medication on larval migration through the lungs. A third aim of the study was to determine if adult cats infected with T. cati developed lung disease. Cats in infected groups were administered five oral doses of L3 T. cati larvae. Four-month-old specific pathogen free (SPF) kittens were divided into three groups (six per group): an infected untreated group, an uninfected untreated control group, and an infected treated group (topical moxidectin and imidacloprid, Advantage Multi for Cats, Bayer Healthcare LLC). Six 2- to 3-year-old adult multiparous female SPF cats were an infected untreated adult group. The cats were evaluated by serial CBCs, bronchial-alveolar lavage (BAL), fecal examinations, thoracic radiographs, and thoracic computed tomography (CT) scans and were euthanized 65 days after the initial infection. Adult T. cati were recovered in infected untreated kittens (5/6) and infected untreated adults (5/6) in numbers consistent with natural infections. Eggs were identified in the feces of most but not all cats with adult worm infections. No adult worms were identified in the uninfected controls or the infected treated group. All cats in the infected groups, including treated cats and untreated cats without adult worms, had lung pathology based on evaluation of radiography, CT scans, and histopathology. The infected cats demonstrated a transient peripheral eosinophilia and marked eosinophilic BAL cytology, but normal bronchial reactivity based on in vivo CT and in vitro ring studies. Lung lesions initially identified by CT on day 11 were progressive. Thoracic radiographs in infected cats had a diffuse bronchial-interstitial pattern and enlarged pulmonary arteries. Pulmonary arterial, bronchial, and interstitial disease were prominent histological findings. Infected treated cats had a subtle attenuation but not prevention of lung disease compared to infected cats. Significant lung disease in kittens and adult cats is associated with the early arrival of T. cati larvae in the lungs and is independent of the development of adult worms in the intestine. These data suggest that while the medical prevention of the development of adult parasites after oral exposure to T. cati is obviously beneficial, this practice even with good client compliance will not prevent the development of lung disease which can alter clinical diagnostic methods.

TGF-ß-responsive myeloid cells suppress type 2 immunity and emphysematous pathology after hookworm infection.

Transforming growth factor ß (TGF-ß) regulates inflammation, immunosuppression, and wound-healing cascades, but it remains unclear whether any of these functions involve regulation of myeloid cell function. The present study demonstrates that selective deletion of TGF-ßRII expression in myeloid phagocytes i) impairs macrophage-mediated suppressor activity, ii) increases baseline mRNA expression of proinflammatory chemokines/cytokines in the lung, and iii) enhances type 2 immunity against the hookworm parasite Nippostrongylus brasiliensis. Strikingly, TGF-ß-responsive myeloid cells promote repair of hookworm-damaged lung tissue, because LysM(Cre)TGF-ßRII(flox/flox) mice develop emphysema more rapidly than wild-type littermate controls. Emphysematous pathology in LysM(Cre)TGF-ßRII(flox/flox) mice is characterized by excessive matrix metalloprotease (MMP) activity, reduced lung elasticity, increased total lung capacity, and dysregulated respiration. Thus, TGF-ß effects on myeloid cells suppress helminth immunity as a consequence of restoring lung function after infection.

Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type immunity.

Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla(-/-) mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla(-/-) mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla(-/-) mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla(-/-) mice developed stronger Th2 responses, which could be reversed by exogenous rRelmalpha treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.

An aspergilloma in an echinococcal cyst cavity.

Aspergilloma is a saprophytic infection which can colonize preexisting lung cavities. The most common underlying diseases are tuberculosis, sarcoidosis, cavitary lung cancer, etc. Although aspergilloma can also occur in operated hydatid cyst cavities, only a few cases have been reported in literature. A 32-year-old female patient underwent cystectomy for the diagnosis of perforated intraparenchymal giant hydatid cyst located in the right upper lobe, reaching down to the hilum. Capitonnage was not performed and it was observed that a residual cavity remained in the cystectomy area. The patient was discharged; however, during clinical and radiological follow-ups, it was found that the residual cyst cavity had expanded. As it was thought that one of the drainage bronchi in the cyst cavity could have opened, the patient was reoperated. During the operation, it was noted that purulent fluid and necrotic tissues were present in the cystic cavity. It was seen that the posterior upper lobe segment was consolidated and not ventilated. Contents of the cavity were removed and the posterior upper lobe segment was resected. Histopathological examination revealed that the tissue in the cavity was that of an aspergilloma, and that chronic organized pneumonia and diffuse interstitial fibrosis were present in the resected segment. Refraining from surgical obliteration (capitonnage) of cyst cavities in cases of giant hydatid cysts extending to the hilum can lead to opportunistic infections such as aspergilloma.

Induction of tumour necrosis factor, interleukin-1beta and matrix metalloproteinases in pulmonary fibrosis of rats infected with Angiostrongylus cantonensis.

In angiostrongyliasis, chronic parasite-induced granuloma formation can lead to tissue destruction and fibrosis. Here, the histomorphology of granulomatous fibrosis and proteinase production in the lungs of Angiostrongylus cantonensis-infected Sprague-Dawley rats were investigated. The relationship between metalloproteinases and granulomatous fibrosis was investigated following infection of each rat with 60 infective larvae. Granulomata and fibrosis were marked in the lungs of rats on day 180 post-inoculation. Reverse transcriptase polymerase chain reaction of lung mRNA showed an up-expression of proinflammatory cytokine including tumour necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta). According to Western blot analysis, matrix metalloproteinase-2 (MMP-2) proenzyme was presented in the lungs of uninfected and infected rats, and partial conversion of 72 kDa proenzyme to the 64 kDa active form occurred in infected rats. In addition, increased protein levels of MMP-9 and MMP-13 were detected in infected lungs, but were undetectable in controls. The results suggest that TNF-alpha, IL-1beta, MMP-2, -9, and -13 may be associated with the granulomatous fibrosis.

Matrix metalloproteinase-2 and -9 in the granulomatous fibrosis of rats infected with Angiostrongylus cantonensis.

The histomorphology of granuloma formation and gelatinase production were investigated in the brains, hearts, lungs and livers of Sprague-Dawley rats infected with Angiostrongylus cantonensis. The relationships between two gelatinases and granulomatous fibrosis were explored, following infection of each rat with 60 infective larvae of the nematode. Worm recovery from the brain was maximal on day 15 post-inoculation whereas peak recovery from the lungs was maximal 75 days later, on day 90. The granulomatous reactions and fibrosis were marked in the lungs but only mild, if present at all, in the brain, heart and liver. Gelatin zymography revealed that matrix metalloproteinase2 (MMP-2) was present, at all time-points, in the heart and lungs, although only in the lungs was there partial conversion of the 72-kDa pro-enzyme to the 64-kDa active form during granulomatous fibrosis. The activity of the MMP-9 pro-enzyme was significantly higher at the time-points when granuloma formation was observed than at other times. Immuno-histochemistry revealed MMP-2 and MMP-9 within the lung granulomas, around infiltrating leucocytes and the epithelial cells of the alveoli. As the granulomatous fibrosis appeared to be strongly associated with MMP-2 and MMP-9, these enzymes may be useful markers in the lungs of rats infected with A. cantonensis.

[Disseminated strongyloidiasis associated with pulmonary fibrosis and gastrointestinal bleeding]. / Anguillulose maligne associée à une fibrose pulmonaire et une hémorragie digestive.

Strongyloidiasis is a parasitic disease that can be lethal in immunosuppressed patients especially if lung fibrosis is associated, which has been rarely reported. We report the case of a patient treated with corticosteroids for pulmonary fibrosis who developed disseminated strongyloidiasis revealed by massive gastrointestinal bleeding. Diagnosis was based on histological analysis of gastrointestinal biopsies and broncho-alveolar lavage. Treatment improved digestive features as well as respiratory function.

Pulmonary strongyloidiasis presenting as chronic bronchitis leading to interlobular septal fibrosis and cured by treatment.

Two patients presented with long-standing chronic bronchitis and exertional dyspnoea of 5 and 3 months' duration, respectively, and had interlobular septal fibrosis on chest high resolution CT. In the past both had lived in areas in which Strongyloides stercoralis was known to be endemic. Serological tests confirmed the diagnosis of pulmonary strongyloidiasis, and both patients were treated with anti-helminthic medications, including albendazole and ivermectin. Following this there was complete resolution of both symptomatic and radiological manifestations of their disease. An awareness of the possibility of Strongyloides infection presenting with respiratory symptoms in patients exposed to this parasite is important in the management of such patients.

The effect of ketoconazole on pulmonary pathology associated with dead Dirofilaria immitis.

The involvement of thromboxane and lipoxygenase in the regulation of pulmonary lesions and immune responses was investigated in dogs given ketoconazole and exposed to dead adult Dirofiliara immitis. Immunopathological reactions to the dead filariae were monitored by light and transmission electron microscopy and serology. When compared with control tissues, ketoconazole administration enhanced the level of pulmonary haemorrhage and early parenchymal fibrosis associated with dead adult filariae. Ultrastructurally, alveolar capillaries were filled with erythrocyte aggregations and proteinaceous material. These results suggested that an intact thromboxane and lipoxygenase pathway within the arachidonic acid system is necessary to minimize the effect of dead D. immitis in this pulmonary artery model.

Effect of diethylcarbamazine on the alveolitis of tropical eosinophilia.

Bronchoalveolar lavage studies in 33 patients with acute untreated tropical eosinophilia have demonstrated intense eosinophilic alveolitis. Following treatment with a standard 3-week course of diethylcarbamazine, there was a significant fall in lung eosinophils (p less than 0.001). However, a mild alveolitis characterised by hypercellular lavage fluid due to a significant increase in absolute alveolar macrophages (p less than 0.001) and due to an increase in both the absolute number (p less than 0.01) and percentage of eosinophils (p = 0.02) was persisting at 1 month despite treatment. Long-term follow-up is essential to know the fate of alveolitis.

Naturally occurring apicomplexan acute interstitial pneumonitis in thick-billed parrots (Rhynchopsitta pachyrhyncha).

This report describes acute interstitial pneumonitis due to an apicomplexan parasite with schizogony in endothelial cells of pulmonary vessels accompanied by early and metrocyte stages of sarcocysts in the heart of a thick-billed parrot (Rhynchopsitta pachyrhyncha). The pattern of this disease is similar to that of the acute phase (approximately 10-15 days postinoculation) of experimental infections of budgerigars, Melopsittacus undulatus, with high doses of sporocysts of Sarcocystis falcatula.