Ketoprofen affects the mammary immune response in dairy cows in vivo and in vitro

Abstract

Nonsteroidal anti-inflammatory drugs are commonly administered parenterally in addition to antimicrobial mastitis therapy to increase the well-being of the diseased animal. As mastitis is usually a localized infection of mammary tissue, we tested the hypothesis that a local administration of nonsteroidal anti-inflammatory drugs through the teat canal could have anti-inflammatory effects on the affected area. We investigated the effects of intramammarily administered ketoprofen (KET) during an LPS-induced immune response on somatic cell count (SCC) and blood-milk barrier integrity. In addition, we investigated the effects of KET on the mRNA abundance of immune factors and their prostaglandin E2 secretion in primary bovine mammary epithelial cells in vitro. Six cows received 0.2 µg of LPS (serotype O26:B6) together with 50 mg of KET into one quarter and LPS only in the opposing quarter. The increase of SCC and of serum albumin (SA) and IgG concentrations and the increase of lactate dehydrogenase (LDH) activity in milk induced by LPS were lower in quarters that received KET in addition. In 3 cows, intramammary KET (50 mg) without additional LPS did not affect SCC, SA, IgG, and LDH in milk. Effects of KET on the immune response of mammary epithelial cells in vitro were investigated in cells from 3 cows challenged with or without LPS (0.2 µg/mL) and with or without additional KET in 2 concentrations (1.25 or 2.5 mg/mL). Ketoprofen reduced the LPS-induced increase of mRNA abundance of tumor necrosis factor α, IL-8, serum amyloid A, and cyclooxygenase-2. The mRNA abundance of cyclooxygenase-1 and prostaglandin E synthase was reduced in cells without LPS challenge by addition of KET at 2.5 mg/mL. Furthermore, the LPS-induced secretion of prostaglandin E2 of mammary epithelial cells into the supernatant could not be detected if KET was added. The results demonstrate that intramammary KET diminishes the increase of SCC and reduces the impairment of the blood-milk barrier (based on SA and LDH in milk), leading to a reduced IgG concentration in milk during LPS-induced mastitis. In mammary epithelial cells, KET limits the expression of several immune factors that are increased during an immune response. In summary, intramammary administration of KET reduces the inflammatory response in the mammary gland. However, it remains unclear whether the inhibited transfer of immune cells and IgG from blood into milk after KET administration would reduce the success of the immune defense in infectious mastitis.

Meloxicam affects the inflammatory responses of bovine mammary epithelial cells

“…Results of the present study show that the addition of MEL to bovine MEC diminishes the processes of inflammation not only at the mRNA level but also at the protein level. In contrast to our results, Dan et al (2018) did not find any change in the synthesis of PGE 2 using similar doses (1.25 and 2.5 mg/mL) of ketoprofen in addition to LPS-challenged MEC, letting us conclude that the selectivity and type of NSAID are essential for this response.…”

“…When cells received 1.5 mg/mL MEL in addition to the PAMP, the mRNA abundance of most cytokines was similar to nontreated controls at all time points. Even if more attenuate, Dan et al (2018) found similar results in mRNA abundance of TNF and IL-8 of MEC treated with 0.2 µg/mL LPS in combination with 1.25 or 2.5 mg/mL ketoprofen, a non-selective NSAID. In an inflamed mammary gland it could be interesting to decrease the exacerbated production of leukocyte chemoattractants by MEL because it is known that excessive neutrophil infiltration leads to production of reactive oxygen species, tissue destruction, and mortality (Kolaczkowska and Kubes, 2013).…”

“…Primary mammary epithelial cells in culture were shown to mirror the mammary immune response to different pathogens by expression of different immune factors (Wellnitz and Kerr, 2004;Griesbeck-Zilch et al, 2008;Dan et al, 2018). Cells of 4 cows cultured separately were used to provide the biological repeatability.…”

A multicomponent herbal feed additive improves somatic cell counts in dairy cows ‐ a two stage, multicentre, placebo‐controlled long‐term on‐farm trial

“…On the one hand, antioxidants protect immune cells from oxidative stress, making them more successful in eliminating pathogens (Sordilllo, ) and thus leading to lower SCC. On the other hand, it is known from recent studies that non‐steroidal anti‐inflammatory drugs (NSAID) are able to reduce SCC during and after acute or induced mastitis (Dan, Bruckmaier, & Wellnitz, ; McDougall, Bryan, & Tiddy, ). These findings may indicate that overshooting immune reactions of the mammary gland could be counterproductive for the restorative process of the mammary gland after an inflammatory process.…”

Efficacy of ketoprofen for treatment of spontaneous, culture-negative, mild cases of clinical mastitis: A randomized, controlled superiority trial

“…Because ketoprofen is characterized by a rapid onset of action, a short plasma half-life, low toxicity (Kantor, 1986), and no need for milk withdrawal after treatment, it could be justified for clinical mastitis therapy. Although some studies have evaluated the efficacy of ketoprofen for clinical mastitis treatment (Shpigel et al, 1994;Banting et al, 2008;Dan et al, 2018), outcomes such as risk of clinical and microbiological cure and relapse and recurrence of clinical mastitis have not been studied. To our knowledge, the efficacy of ketoprofen to treat culture-negative clinical mastitis cases following OFC results has not been studied.…”