Bromelain treatment decreases neutrophil migration to sites of inflammation

Abstract

Bromelain, a mixture of proteases derived from pineapple stem, has been reported to have therapeutic benefits in a variety of inflammatory diseases, including murine inflammatory bowel disease. The purpose of this work was to understand potential mechanisms for this anti-inflammatory activity. Exposure to bromelain in vitro has been shown to remove a number of cell surface molecules that are vital to leukocyte trafficking, including CD128a/CXCR1 and CD128b/CXCR2 that serve as receptors for the neutrophil chemoattractant IL-8 and its murine homologues. We hypothesized that specific proteolytic removal of CD128 molecules by bromelain would inhibit neutrophil migration to IL-8 and thus decrease acute responses to inflammatory stimuli. Using an in vitro chemotaxis assay, we demonstrated a 40% reduction in migration of bromelain-vs. sham-treated human neutrophils in response to rhIL-8. Migration to the bacterial peptide analog fMLP was unaffected, indicating that bromelain does not induce a global defect in leukocyte migration. In vivo bromelain treatment generated a 50 -85% reduction in neutrophil migration in 3 different murine models of leukocyte migration into the inflamed peritoneal cavity. Intravital microscopy demonstrated that although in vivo bromelain treatment transiently decreased leukocyte rolling, its primary long-term effect was abrogation of firm adhesion of leukocytes to blood vessels at the site of inflammation. These changes in adhesion were correlated with rapid re-expression of the bromelain-sensitive CD62L/L-selectin molecules that mediate rolling following in vivo bromelain treatment and minimal re-expression of CD128 over the time period studied. Taken together, these studies demonstrate that bromelain can effectively decrease neutrophil migration to sites of acute inflammation and support the specific removal of the CD128 chemokine receptor as a potential mechanism of action.

Evaluation of Anti-Inflammatory Activity of Pseudananas macrodontes (Morr.) Harms (Bromeliaceae) Fruit Extract in Rats

“…All doses tested produced signifi cant inhibition after 7 h. It is known that indomethacin inhibits prostaglandins production (by inhibition of COX-1), while bromelain, in other experimental models, has been shown to reduce the production of NO (Wen et al, 2006) and prostaglandins (Bhui et al, 2011), as well as neutrophil migration (Fitzhugh et al, 2008). These results allow us to conclude that PPE Pm acts preferentially on the second rather than the fi rst phase of carrageenaninduced edema, which could be explained by a better bioavailability and/or increased specifi city against the release/action of mediators involved in the second phase (neutrophils, prostaglandins, and NO), whose production usually peaks between 3 and 6 h after injection of carrageenan (Salvemini et al, 1996).…”

“…Since the anti-infl ammatory mechanism of bromelain has been attributed to its proteolytic activity (Fitzhugh et al, 2008;Hale and Haynes, 1992;Mynott et al, 1999;Hale et al, 2000Hale et al, , 2005, the higher dose of PPE Pm (on weight basis) in the acute infl ammatory assays was chosen to contain proteolytic activity equal to that of bromelain ( 30 CU/kg BW). The observation that, on this basis, the effects of the two preparations were signifi cantly similar, supports the notion that proteases are responsible for their anti-infl ammatory activities.…”

“…The anti-infl ammatory activity of bromelain involves an increase in the fi brinolytic activity, enhancement of plasmin concentration by activation of the conversion of plasminogen to plasmin, decrease of the levels of plasma fi brinogen, bradykinin, and prekallikrein (Maurer, 2001), decrease of prostaglandin E 2 (PGE 2 ), thromboxane A 2 , and substance P levels (Vellini et al, 1986;Gaspani et al, 2002), as well as the modulation of cell surface molecules involved in migration (Fitzhugh et al, 2008) and cellular activation (Hale and Haynes, 1992;Mynott et al, 1999;Hale et al, 2002), and reduction of cyclooxygenase-2 (COX-2) expression by inhibing the activation of nuclear factor kappa-B (NF-KB) (Bhui et al, 2011). Even though the mechanism of the anti-infl ammatory action of bromelain has not yet been defi nitively elucidated, its proteolytic activity appears to be implicated (Fitzhugh et al, 2008;Hale and Haynes, 1992;Mynott et al, 1999;Hale et al, 2002Hale et al, , 2005.…”

“…Even though the mechanism of the anti-infl ammatory action of bromelain has not yet been defi nitively elucidated, its proteolytic activity appears to be implicated (Fitzhugh et al, 2008;Hale and Haynes, 1992;Mynott et al, 1999;Hale et al, 2002Hale et al, , 2005. For fi cin and bromelain, Netti et al (1972) found the degree of the inhibition of rat paw edema induced by different agents -carrageenan, serotonin, dextran, and brewer's yeast -similar or better than that achieved with indomethacin, acetylsalicylic acid, and phenylbutazone.…”

Use of honey associated with Ananas comosus (Bromelin) in the treatment of acute irritative cough

“…In this context, products derived from Ananas comosus extract (rich in Bromelin) and honey have shown promising results, as they contain proteolytic enzymes such as trypsin, chymotrypsin and Bromelin 7. Bromelin is the generic name for the family of proteolytic enzymes containing the sulfhydryl radical derived from A. comosus , the pineapple plant, which also has nonproteolytic enzymes, with significant topical action in the respiratory mucosa 7…”