Effects of experimental asthma on inflammation and lung mechanics in sickle cell mice.
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.
Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. kpritch@mcw.edu
Kirkwood A
KA
Pritchard
Thom R
TR
Feroah
Sandhya D
SD
Nandedkar
Sandra L
SL
Holzhauer
William
W
Hutchins
Marie L
ML
Schulte
Robert C
RC
Strunk
Michael R
MR
Debaun
Cheryl A
CA
Hillery
D000403:Airway Resistance; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D001249:Asthma / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D016085:Bronchoconstrictor Agents; D003124:Colorimetry; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000276:immunology; D006441:Hemoglobin A / Q000235:genetics / Q000378:metabolism; D006451:Hemoglobin, Sickle / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D018836:Inflammation Mediators / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D016210:Methacholine Chloride; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin; D011014:Pneumonia / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D011175:Positive-Pressure Respiration; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016085:Bronchoconstrictor Agents; D016207:Cytokines; D006451:Hemoglobin, Sickle; D018836:Inflammation Mediators; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D010047:Ovalbumin; D006441:Hemoglobin A; D007770:L-Lactate Dehydrogenase