Neutrophil histamine contributes to inflammation in mycoplasma pneumonia.
Mycoplasmas cause chronic inflammation and are implicated in asthma. Mast cells defend against mycoplasma infection and worsen allergic inflammation, which is mediated partly by histamine. To address the hypothesis that mycoplasma provokes histamine release, we exposed mice to Mycoplasma pulmonis, comparing responses in wild-type and mast cell-deficient KitW-sh/KitW-sh (W-sh) mice. Low histamine levels in uninfected W-sh mice confirmed the conventional wisdom that mast cells are principal sources of airway and serum histamine. Although mycoplasma did not release histamine acutely in wild-type airways, levels rose up to 50-fold above baseline 1 week after infection in mice heavily burdened with neutrophils. Surprisingly, histamine levels also rose profoundly in infected W-sh lungs, increasing in parallel with neutrophils and declining with neutrophil depletion. Furthermore, neutrophils from infected airway were highly enriched in histamine compared with naive neutrophils. In vitro, mycoplasma directly stimulated histamine production by naive neutrophils and strongly upregulated mRNA encoding histidine decarboxylase, the rate-limiting enzyme in histamine synthesis. In vivo, treatment with antihistamines pyrilamine or cimetidine decreased lung weight and severity of pneumonia and tracheobronchitis in infected W-sh mice. These findings suggest that neutrophils, provoked by mycoplasma, greatly expand their capacity to synthesize histamine, thereby contributing to lung and airway inflammation.
Xu
Xiang
X
Cardiovascular Research Institute, Department of Microbiology/Immunology, University of California at San Francisco, and Veterans Affairs Medical Center, San Francisco 94121, USA.
Zhang
Dongji
D
Zhang
Hong
H
Wolters
Paul J
PJ
Killeen
Nigel P
NP
Sullivan
Brandon M
BM
Locksley
Richard M
RM
Lowell
Clifford A
CA
Caughey
George H
GH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001491:Basophils / Q000378:metabolism; D001991:Bronchitis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000382:microbiology; D002452:Cell Count; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006632:Histamine / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D006640:Histidine Decarboxylase / Q000235:genetics; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D045803:Mycoplasma pulmonis / Q000254:growth & development; D009503:Neutropenia / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D009929:Organ Size / Q000187:drug effects; D011019:Pneumonia, Mycoplasma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000276:immunology; D013997:Time Factors
D000911:Antibodies, Monoclonal; C503133:Gr-1 protein, mouse; D006634:Histamine H1 Antagonists; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D006632:Histamine; D019009:Proto-Oncogene Proteins c-kit; D006640:Histidine Decarboxylase