Potential Involvement of Gelatinases and Their Inhibitors inMannheimia haemolyticaPneumonia in Cattle

Abstract

Mannheimia haemolytica infection of the lower respiratory tract of cattle results in a bronchofibrinous pneumonia characterized by massive cellular influx and lung tissue remodeling and scarring. Since altered levels of gelatinases and their inhibitors have been detected in a variety of inflammatory conditions and are associated with tissue remodeling, we examined the presence of gelatinases in lesional and nonlesional lung tissue obtained from calves experimentally infected with M. haemolytica. Lesional tissue had elevated levels of progelatinase A and B and active gelatinase A and B when compared with nonlesional tissue obtained from the same lung lobe. In vitro, M. haemolytica products stimulated production of gelatinase B, but not its activation, by bovine monocytes. Alveolar macrophages showed constitutive production of gelatinase B but no change in response to M. haemolytica products. Bovine neutrophils exposed to M. haemolytica products also released gelatinase B, and there was a significant increase in the activated form of this enzyme. These effects were virtually identical when recombinant O-sialoglycoprotease was used to stimulate these cells. M. haemolytica products also enhanced the expression by bovine monocytes and alveolar macrophages of the tissue inhibitor of metalloproteinase 1. Our results provide evidence that matrix metalloproteinases are activated in lung lesions from cattle with shipping fever and that M. haemolytica virulence products induce production, release, and especially activation of gelatinase B by bovine inflammatory cells in vitro.Bronchofibrinous pneumonia (shipping fever) is a respiratory disease in cattle that is characterized by cellular influx and interalveolar and interlobular fibrosis in the lungs of affected animals (3,7,18,20,64,65). Lung lesions consistently show areas of coagulation necrosis, extensive fibrin deposits, and intense cellular infiltration into the alveoli (5, 63, 65). Economic losses to the beef industry due to shipping fever are estimated at over one billion dollars per year in North America alone (64). Causes of this pneumonic condition are multifactorial, including a combination of stress or viral infection, with a final acute illness due most often to the bacteria Mannheimia (Pasteurella) haemolytica serotype A1 (16,39,64). M. haemolytica serotype A1 is a normal resident of the upper respiratory flora of most cattle, but when aspirated into the lower respiratory tract of immunocompromised animals, it is able to colonize the lungs and induce an inflammatory reaction (65).M. haemolytica was originally classified in the genus Pasteurella (50), but more recent genetic characterization has resulted in reclassification of 11 serotypes of biotype A in the new genus Mannheimia (4, 9). M. haemolytica is a trehalosenegative coccobacillus in which heat-stable lipopolysaccharide (LPS) constitutes 12 to 25% of the dried cell wall (66). During logarithmic growth, the bacteria produce and release a heatlabile exotoxin, termed leukotoxin (Lkt), and a heat-labile en...

Serum proteins and lipids in mild form of calf bronchopneumonia: candidates for reliable biomarkers

“…Calf bronchopneumonia is characterized by massive cellular infl ux and lung tissue remodeling and matrix metalloproteases have been studied as key factors in tissue remodeling. Thus, increased concentration and activity of gelatinases (MMP2 and MM9) were detected in lung lesion of calves with experimentally induced M. haemolytica pneumonia [4] and in tracheobronchial lavage fl uid of calves with concurrent infections of P. multocida and M. bovirhinis [49]. Hinds et al [30] using intravenous application of E. coli lipopolysaccharide as a model for acute phase protein responses showed that covalent MMP-9 haptoglobin complex (Hp-MMP-9) was detected in the serum before and declined more rapidly than other acute phase proteins, and assumed that Hp-MMP9 complex can be early and accurate markers of calf respiratory diseases.…”

“…Even nowadays the diagnosis of calf bronchopneumonia is based mostly on clinical observation. Isolation of causative microbiological agents and hematological, biochemical, and immunological analyses have been widely applied in epidemiological surveys and basic and applied research of the disease pathogenesis [2][3][4][5][6][7][8][9][10][11]. Most of these methods are available for veterinary practice; however, they are extremely rarely, if at all, used for the diagnosis of calf bronchopneumonia.…”

Invited review: Relationship between cattle transport, immunity and respiratory disease

“…Elevated levels of myeloperoxidase, elastase, alkaline phosphatase and nitric oxide activity, which are all known to contribute to lung injury, were found in neutrophils of heifers with respiratory tract infections (Wessely-Szponder et al, 2004). Matrix metalloproteinases (MMPs), especially gelatinases, released from neutrophil tertiary granules have been implicated in tissue damage and have been found produced by neutrophils that were isolated from lung lesions and exposed to M. (Pasteurella) haemolytica products (Starr et al, 2004).…”

Serum concentrations of haptoglobin and haptoglobin-matrix metalloproteinase 9 (Hp-MMP 9) complexes of bovine calves in a bacterial respiratory challenge model

“…MMP 9 is a collagenase belonging to the gelatinase B group [ 5 ]. The gelatinase B group is a family of MMP’s that are zinc dependent proteinases capable of degrading at least one component of the extracellular matrix or basement membrane.…”

“…This capability assists in the migration of white blood cells, mostly neutrophils, from the blood to the site of inflammation [ 4 ]. MMP 9 is stored in tertiary granules within the bovine neutrophils and is released when neutrophil degranulation is induced by either chemical or microbial stimuli [ 1 , 5 , 10 , 11 ]. After release, MMP 9 is able to cleave interleukin 8, if present in the microenvironment into active interleukin 8.…”