ovalbumin and Anemia--Sickle-Cell

Asthma appears to be a common comorbid condition in children with sickle cell disease (SCD), and such individuals may be at a higher risk for increased morbidity and mortality. However, several reports have indicated that asthma severity is not particularly high in those with SCD, and airway hyperreactivity and wheeze may be independently associated with SCD. In SCD mice, exacerbated allergic airway disease (AAD) has been observed in response to the model antigen ovalbumin (OVA). We sought to determine if allergic lung inflammation is also exacerbated in SCD mice when they are exposed to the human allergen, house dust mite (HDM).. Eosinophil counts in bronchoalveolar lavage fluid were determined by cytocentrifugation and increased in both wild-type (WT) and SCD mice after acute exposure to a high dose (25 µg) of HDM, which then decreased in chronically exposed mice. WT mice exposed to a low dose of HDM (1 µg) followed the same pattern of eosinophil flux, but SCD mice did not induce much eosinophilia after acute exposure to HDM. As was observed in previous studies, lung lesions similarly increased in severity in both WT and SCD mice after acute exposure to HDM, which remained elevated after chronic exposure. Furthermore, serum HDM-specific IgE titers similarly increased and selected serum cytokines were similar in both WT and SCD mice.. These results contrast with previous reports of exacerbated AAD in SCD mice exposed to OVA and support the alternative hypothesis that asthmatic responses are normal in those with SCD.

Topics: Allergens; Anemia, Sickle Cell; Animals; Bronchoalveolar Lavage Fluid; Cytokines; Female; Immunoglobulin E; Leukocyte Count; Male; Mice, Transgenic; Ovalbumin; Pyroglyphidae; Respiratory Hypersensitivity

Comorbid asthma in sickle cell disease (SCD) confers higher rates of vaso-occlusive pain and mortality, yet the physiological link between these two distinct diseases remains puzzling. We used a mouse model of SCD to study pulmonary immunology and physiology before and after the induction of allergic airway disease (AAD). SCD mice were sensitized with ovalbumin (OVA) and aluminum hydroxide by the intraperitoneal route followed by daily, nose-only OVA-aerosol challenge to induce AAD. The lungs of naive SCD mice showed signs of inflammatory and immune processes: (1) histologic and cytochemical evidence of airway inflammation compared with naive wild-type mice; (2) bronchoalveolar lavage (BAL) fluid contained increased total lymphocytes, %CD8+ T cells, granulocyte-colony stimulating factor, interleukin 5 (IL-5), IL-7, and chemokine (C-X-C motif) ligand (CXCL)1; and (3) lung tissue and hilar lymph node (HLN) had increased CD4+, CD8+, and regulatory T (Treg) cells. Furthermore, SCD mice at AAD demonstrated significant changes compared with the naive state: (1) BAL fluid with increased %CD4+ T cells and Treg cells, lower %CD8+ T cells, and decreased interferon gamma, CXCL10, chemokine (C-C motif) ligand 2, and IL-17; (2) serum with increased OVA-specific immunoglobulin E, IL-6, and IL-13, and decreased IL-1α and CXCL10; (3) no increase in Treg cells in the lung tissue or HLN; and (4) hyporesponsiveness to methacholine challenge. In conclusion, SCD mice have an altered immunologic pulmonary milieu and physiological responsiveness. These findings suggest that the clinical phenotype of AAD in SCD mice differs from that of wild-type mice and that individuals with SCD may also have a unique, divergent phenotype perhaps amenable to a different therapeutic approach.

Topics: Anemia, Sickle Cell; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Eosinophils; Female; Hemizygote; Hypersensitivity; Inflammation; Leukocyte Count; Lung; Mice, Inbred C57BL; Mucus; Ovalbumin; T-Lymphocytes

Children with sickle cell disease (SCD) are susceptible to recurrent infections, which are often life threatening and necessitate frequent vaccinations. Given the altered baseline immunity and proinflammatory state associated with SCD, we sought to determine the relative safety and efficacy of vaccination in transgenic SCD mice.. Eight-week-old SCD mice were vaccinated with ovalbumin and aluminum hydroxide weekly for 3 wk by the intraperitoneal or intramuscular route. One week after the third vaccination, serum cytokines/chemokines, immunoglobulins, and bronchoalveolar lavage fluid cytokines were measured.. Only SCD mice were prone to mortality associated with vaccination, as 40% of the animals died after the intraperitoneal vaccinations and 50% died after the intramuscular vaccinations. Serum IgG2b and IgM were significantly lower in SCD mice than in C57BL/6 mice after vaccination, but ovalbumin-specific IgE was significantly higher. Serum interleukin (IL)-1α, IL-2, IL-5, macrophage inflammatory protein 1α, and granulocyte macrophage-colony stimulating factor were significantly lower in SCD mice than in C57BL/6 mice after vaccination, whereas bronchoalveolar lavage fluid IL-1β and IL-6 were increased.. Mice with SCD appear to have a dysregulated immune response to vaccination. Thus, the relative safety and immunogenicity of vaccination should be studied in greater detail in the context of SCD.

Topics: Aluminum Hydroxide; Analysis of Variance; Anemia, Sickle Cell; Animals; Bronchoalveolar Lavage Fluid; Cytokines; Female; Immunoglobulins; Injections, Intramuscular; Mice; Mice, Transgenic; Ovalbumin; Vaccination

Experimental asthma increases eosinophil and collagen deposition in the lungs of sickle cell disease (SCD) mice to a greater extent than in control mice. However, the effects of asthma on inflammation and airway physiology remain unclear. To determine effects of asthma on pulmonary inflammation and airway mechanics in SCD mice, hematopoietic stem cell transplantation was used to generate chimeric SCD and hemoglobin A mice. Experimental asthma was induced by sensitizing mice with ovalbumin (OVA). Airway mechanics were assessed using forced oscillation techniques. Mouse lungs were examined histologically and physiologically. Cytokine, chemokine, and growth factors in bronchoalveolar lavage fluid were determined by multiplex. IgE was quantified by ELISA. LDH was quantified using a colorimetric enzymatic assay. At baseline (nonsensitized), chimeric SCD mice developed hemolytic anemia with sickled red blood cells, mild leukocytosis, and increased vascular endothelial growth factor and IL-13 compared with chimeric hemoglobin A mice. Experimental asthma increased perialveolar eosinophils, plasma IgE, and bronchoalveolar lavage fluid IL-1β, IL-4, IL-6, and monocyte chemotactic protein 1 in chimeric hemoglobin A and SCD mice. IFN-γ levels were reduced in both groups. IL-5 was preferentially increased in chimeric SCD mice but not in hemoglobin A mice. Positive end-expiratory pressures and methacholine studies revealed that chimeric SCD mice had greater resistance in large and small airways compared with hemoglobin A mice at baseline and after OVA sensitization. SCD alone induces a baseline lung pathology that increases large and small airway resistance and primes the lungs to increased inflammation and airway hyperresponsiveness after OVA sensitization.

Topics: Airway Resistance; Anemia, Sickle Cell; Animals; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Colorimetry; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Eosinophils; Hemoglobin A; Hemoglobin, Sickle; Humans; Immunoglobulin E; Inflammation Mediators; L-Lactate Dehydrogenase; Lung; Methacholine Chloride; Mice; Mice, Inbred C57BL; Mice, Transgenic; Ovalbumin; Pneumonia; Positive-Pressure Respiration; Vascular Endothelial Growth Factor A

Asthma is a comorbid condition associated with increased rates of pain, acute chest syndrome, and premature death in human sickle cell disease (SCD). We developed an experimental asthma model in SCD and control mice expressing either normal human or murine hemoglobin to determine its effect on mortality and lung pathology. To induce lung inflammation, experimental mice were sensitized to ovalbumin (OVA) by subcutaneous OVA implantation (Sen), allowed 2 weeks to recover, and then divided into 2 groups, each receiving over a subsequent 10-day period the same dosage of aerosolized OVA but 2 different levels of exposure: 15 minutes (LoSen) and 30 minutes (HiSen). During recovery, 10% of SCD mice died compared with no deaths in control mice. An additional 30% of HiSen SCD mice died during aerosolization compared with 10% in LoSen SCD. Histologic indices of lung inflammation (eg, eosinophil recruitment, airway and vessel wall thickening, and immunoreactive TGFbeta and fsp-1) and bronchial alveolar lavage fluid eosinophil peroxidase activity differentially increased in sensitized mice compared with unsensitized mice. Our findings indicate SCD mice with experimentally induced asthma are more susceptible to death and pulmonary inflammation compared with control mice, suggesting that asthma contributes significantly to morbidity and mortality in SCD.

Topics: Anemia, Sickle Cell; Animals; Asthma; Disease Models, Animal; Hemoglobins; Humans; Inflammation; Lung; Mice; Ovalbumin; Survival Rate

Effects of 3,5-dimethoxy-4-hydroxybenzoic acid and 2,3,4-trihydroxyacetophenone were studied on haemoglobin S (Hb S) polymerisation, analgesia and inflammation using Hb S solution, rats and mice. UV spectrophotometric procedure was used to monitor the polymerization of the Hb S. Acetic acid induced writhing in mice and egg albumin induced rat paw edema procedures were used to evaluate analgesic and anti-inflammatory activities of the compounds respectively. The results indicate that both drugs inhibit the process of polymerization significantly, possibly by direct action on the Hb S molecules. The drugs inhibited acetic acid induced pain and decreased egg albumin induced oedema. It is concluded that 3,5-dimethoxy-4-hydroxybenzoic acid and 2,3,4-trihydroxyacetophenone may have some value in the management of sickle cell disease.

Topics: Acetic Acid; Acetophenones; Analgesics; Anemia, Sickle Cell; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antisickling Agents; Edema; Female; Guinea Pigs; Hemoglobin, Sickle; Humans; Hydroxybenzoates; Lethal Dose 50; Male; Mice; Ovalbumin; Pain; Rabbits; Rats; Rats, Wistar

The levels of antibodies of the IgG, IgA and IgM isotypes reacting against ovoalbumin (OVA), gliadin (GL) and cow's milk proteins (CMP), were determined by ELISA in sera from a group of adult patients with sickle cell anemia (SCA) bearing homozygous Ss hemoglobinopathy and from matched health donors. Only patients with steady-state disease were included in the study. Increased amounts of IgG and IgA reacting with OVA, GL and CMP were observed in the group of patients as compared with the controls. In contrast, the levels of IgM antibodies against each of the three dietary antigens were similar in patients and controls. Increased levels of IgG and IgA antibodies against dietary antigens in SCA may result from enhanced permeability of the gut mucosa to macromolecules of dietary origin as a consequence of microinfarctions, chronic polyclonal B cell activation and/or diminished inhibitory control of antibody synthesis.

Topics: Adult; Anemia, Sickle Cell; Antibodies; Female; Gliadin; Humans; Immunoglobulin Isotypes; Male; Milk Proteins; Ovalbumin