Vaccination of Cattle with the N Terminus of LppQ of Mycoplasma mycoides subsp. mycoides Results in Type III Immune Complex Disease upon Experimental Infection

Contagious bovine pleuropneumonia (CBPP) is a serious respiratory disease of cattle caused by Mycoplasma mycoides subsp. mycoides. Current vaccines against CBPP induce short-lived immunity and can cause severe postvaccine reactions. Previous studies have identified the N terminus of the transmembrane lipoprotein Q (LppQ-N') of M. mycoides subsp. mycoides as the major antigen and a possible virulence factor. We therefore immunized cattle with purified recombinant LppQ-N' formulated in Freund's adjuvant and challenged them with M. mycoides subsp. mycoides. Vaccinated animals showed a strong seroconversion to LppQ, but they exhibited significantly enhanced postchallenge glomerulonephritis compared to the placebo group (P = 0.021). Glomerulonephritis was characterized by features that suggested the development of antigen-antibody immune complexes. Clinical signs and gross pathological scores did not significantly differ between vaccinated and placebo groups. These findings reveal for the first time the pathogenesis of enhanced disease as a result of antibodies against LppQ during challenge and also argue against inclusion of LppQ-N' in a future subunit vaccine for CBPP

Switching off malignant mesothelioma : exploiting the hypoxic microenvironment

Malignant mesotheliomas are aggressive, asbestos-related cancers with poor patient prognosis, typically arising in the mesothelial surfaces of tissues in pleural and peritoneal cavity. The relative unspecific symptoms of mesotheliomas, misdiagnoses, and lack of precise targeted therapies call for a more critical assessment of this disease. In the present review, we categorize commonly identified genomic aberrations of mesotheliomas into their canonical pathways and discuss targeting these pathways in the context of tumor hypoxia, a hallmark of cancer known to render solid tumors more resistant to radiation and most chemo-therapy. We then explore the concept that the intrinsic hypoxic microenvironment of mesotheliomas can be Achilles’ heel for targeted, multimodal therapeutic intervention

Regional Heterogeneity in Murine Lung Fibroblasts from Normal Mice or Mice Exposed Once to Cigarette Smoke

Chronic obstructive lung disease (COPD) is characterized by matrix deposition in the small airways but matrix loss from the parenchyma, phenomena which must depend on the ability of local fibroblasts to produce matrix after smoke exposure. To investigate this idea, we exposed C57Bl/6 mice once to cigarette smoke or to air (control) and prepared primary cultures of lung fibroblasts by microdissecting large airways (trachea, LAF), medium size airways (major bronchi, MAF) and parenchyma (PF). Control PF showed the lowest rate of wound closure and wound closure was depressed in all lines by a single in vivo smoke exposure. Gene expression of matrix proteins differed considerably among the sites; decorin, which may sequester TGFβ, was markedly higher in PF. PF showed higher intrinsic ratios of pSmad2/Smad2. Smoke caused much greater increases in secreted and matrix deposited collagens 1 and 3 in PF than in LAF or MAF. Expression of Thy-1, a gene that suppresses myofibroblast differentiation, was increased by smoke in PF. We conclude that there is considerable regional heterogeneity in murine lung fibroblasts in terms of matrix production, either basally or after in vivo smoke exposure; that PF have lower ability to repair wounds and higher intrinsic TGFβ signaling; and that a single exposure to smoke produces lasting changes in the pattern of matrix production and wound repair, changes that may be mediated in part by smoke-induced release of TGFβ. However, PF still retain the ability to repair by producing new matrix after a single in vivo smoke exposure

Pharmacological characterisation of anti-inflammatory compounds in acute and chronic mouse models of cigarette smoke-induced inflammation

<p>Abstract</p> <p>Background</p> <p>Candidate compounds being developed to treat chronic obstructive pulmonary disease are typically assessed using either acute or chronic mouse smoking models; however, in both systems compounds have almost always been administered prophylactically. Our aim was to determine whether the prophylactic effects of reference anti-inflammatory compounds in acute mouse smoking models reflected their therapeutic effects in (more clinically relevant) chronic systems.</p> <p>Methods</p> <p>To do this, we started by examining the type of inflammatory cell infiltrate which occurred after acute (3 days) or chronic (12 weeks) cigarette smoke exposure (CSE) using female, C57BL/6 mice (n = 7-10). To compare the effects of anti-inflammatory compounds in these models, mice were exposed to either 3 days of CSE concomitant with compound dosing or 14 weeks of CSE with dosing beginning after week 12. Budesonide (1 mg kg^-1; i.n., q.d.), roflumilast (3 mg kg^-1; p.o., q.d.) and fluvastatin (2 mg kg^-1; p.o., b.i.d.) were dosed 1 h before (and 5 h after for fluvastatin) CSE. These dose levels were selected because they have previously been shown to be efficacious in mouse models of lung inflammation. Bronchoalveolar lavage fluid (BALF) leukocyte number was the primary endpoint in both models as this is also a primary endpoint in early clinical studies.</p> <p>Results</p> <p>To start, we confirmed that the inflammatory phenotypes were different after acute (3 days) versus chronic (12 weeks) CSE. The inflammation in the acute systems was predominantly neutrophilic, while in the more chronic CSE systems BALF neutrophils (PMNs), macrophage and lymphocyte numbers were all increased (p < 0.05). In the acute model, both roflumilast and fluvastatin reduced BALF PMNs (p < 0.01) after 3 days of CSE, while budesonide had no effect on BALF PMNs. In the chronic model, therapeutically administered fluvastatin reduced the numbers of PMNs and macrophages in the BALF (p ≤ 0.05), while budesonide had no effect on PMN or macrophage numbers, but did reduce BALF lymphocytes (p < 0.01). Roflumilast's inhibitory effects on inflammatory cell infiltrate were not statistically significant.</p> <p>Conclusions</p> <p>These results demonstrate that the acute, prophylactic systems can be used to identify compounds with therapeutic potential, but may not predict a compound's efficacy in chronic smoke exposure models.</p

The effect of cigarette smoke exposure on the development of inflammation in lungs, gut and joints of TNFΔARE mice

The inflammatory cytokine TNF-alpha is a central mediator in many immune-mediated diseases, such as Crohn's disease (CD), spondyloarthritis (SpA) and chronic obstructive pulmonary disease (COPD). Epidemiologic studies have shown that cigarette smoking (CS) is a prominent common risk factor in these TNF-dependent diseases. We exposed TNF Delta ARE mice; in which a systemic TNF-alpha overexpression leads to the development of inflammation; to 2 or 4 weeks of air or CS. We investigated the effect of deregulated TNF expression on CS-induced pulmonary inflammation and the effect of CS exposure on the initiation and progression of gut and joint inflammation. Upon 2 weeks of CS exposure, inflammation in lungs of TNF Delta ARE mice was significantly aggravated. However, upon 4 weeks of CS-exposure, this aggravation was no longer observed. TNF Delta ARE mice have no increases in CD4+ and CD8+ T cells and a diminished neutrophil response in the lungs after 4 weeks of CS exposure. In the gut and joints of TNF Delta ARE mice, 2 or 4 weeks of CS exposure did not modulate the development of inflammation. In conclusion, CS exposure does not modulate gut and joint inflammation in TNF Delta ARE mice. The lung responses towards CS in TNF Delta ARE mice however depend on the duration of CS exposure

Asbestos Burden Predicts Survival in Pleural Mesothelioma

Background: Malignant pleural mesothelioma (MPM) is a rapidly fatal asbestos-associated malignancy with a median survival time of &lt; 1 year following diagnosis. Treatment strategy is determined in part using known prognostic factors. Objective: The aim of this study was to examine the relationship between asbestos exposure and survival outcome in MPM in an effort to advance the understanding of the contribution of asbestos exposure to MPM prognosis. Methods: We studied incident cases of MPM patients enrolled through the International Mesothelioma Program at Brigham and Women’s Hospital in Boston, Massachusetts, using survival follow-up, self-reported asbestos exposure (n = 128), and a subset of cases (n = 80) with quantitative asbestos fiber burden measures. Results: Consistent with the established literature, we found independent, significant associations between male sex and reduced survival (p 1,099), suggested a survival duration association among these groups (p = 0.06). After adjusting for covariates in a Cox model, we found that patients with a low asbestos burden had a 3-fold elevated risk of death compared to patients with a moderate fiber burden [95% confidence interval (CI), 0.95–9.5; p = 0.06], and patients with a high asbestos burden had a 4.8-fold elevated risk of death (95% CI, 1.5–15.0; p < 0.01) versus those with moderate exposure. Conclusion: Our data suggest that patient survival is associated with asbestos fiber burden in MPM and is perhaps modified by susceptibility

Cigarette smoke and lipopolysaccharide induce a proliferative airway smooth muscle phenotype

Background: A major feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, which includes an increased airway smooth muscle (ASM) mass. The mechanisms underlying ASM remodelling in COPD are currently unknown. We hypothesized that cigarette smoke (CS) and/or lipopolysaccharide (LPS), a major constituent of CS, organic dust and gram-negative bacteria, that may be involved in recurrent airway infections and exacerbations in COPD patients, would induce phenotype changes of ASM. Methods: To this aim, using cultured bovine tracheal smooth muscle (BTSM) cells and tissue, we investigated the direct effects of CS extract (CSE) and LPS on ASM proliferation and contractility. Results: Both CSE and LPS induced a profound and concentration-dependent increase in DNA synthesis in BTSM cells. CSE and LPS also induced a significant increase in BTSM cell number, which was associated with increased cyclin D1 expression and dependent on activation of ERK 1/2 and p38 MAP kinase. Consistent with a shift to a more proliferative phenotype, prolonged treatment of BTSM strips with CSE or LPS significantly decreased maximal methacholine- and KCl-induced contraction. Conclusions: Direct exposure of ASM to CSE or LPS causes the induction of a proliferative, hypocontractile ASM phenotype, which may be involved in airway remodelling in COPD