Neutrophil accumulation in the lung in alpha 1-antitrypsin deficiency. Spontaneous release of leukotriene B4 by alveolar macrophages.

Hubbard, Richard C.; Fells, G A; Gadek, James E.; Pacholok, Stephen; Humes, John L.; Crystal, Ronald G.

doi:10.1172/jci115391

Cited by 189 publications

(132 citation statements)

References 60 publications

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“…MPO concentrations were higher, as was the chemoattractant LTB 4 . This suggests that LTB 4 may be the major chemoattractant responsible for the increased neutrophil migration and is consistent with previous findings in bronchoalveolar lavage [33]. The source of the LTB 4 is uncertain although HUBBARD et al [33] suggested that it was released from alveolar macrophages as a direct effect of uninhibited elastase due to a 1 ATD.…”

Section: Discussionsupporting

confidence: 86%

“…This suggests that LTB 4 may be the major chemoattractant responsible for the increased neutrophil migration and is consistent with previous findings in bronchoalveolar lavage [33]. The source of the LTB 4 is uncertain although HUBBARD et al [33] suggested that it was released from alveolar macrophages as a direct effect of uninhibited elastase due to a 1 ATD. Indeed, in the current study elastase activity was more readily detected in the a 1 ATD patients irrespective of bacterial colonization and hence would support the suggestion that this may be responsible [33].…”

Section: Discussionsupporting

confidence: 86%

“…The source of the LTB 4 is uncertain although HUBBARD et al [33] suggested that it was released from alveolar macrophages as a direct effect of uninhibited elastase due to a 1 ATD. Indeed, in the current study elastase activity was more readily detected in the a 1 ATD patients irrespective of bacterial colonization and hence would support the suggestion that this may be responsible [33]. The elastase activity was more readily detected in the larger airways in a 1 ATD probably due to the combined effect of the lower concentrations of both a 1 AT and SLPI.…”

Section: Discussionmentioning

confidence: 99%

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Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency

Hill¹,

Bayley²,

Campbell³

et al. 2000

Eur Respir J

104

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Airways inflammation in chronic bronchitis is thought predominantly to be a direct consequence of neutrophil recruitment and release of elastase in response to factors such as cigarette smoke. The aims of this study were to assess the role of smoking and determine whether the serum elastase inhibitor α1‐antitrypsin (α1AT) influenced the process. Airways inflammation was compared between patients with chronic obstructive bronchitis with (n=39) and without (n=42) severe α1AT deficiency. The authors assessed the sputum concentration of the neutrophil chemoattractants interleukin‐8 (IL‐8) and leukotriene (LT)B4, myeloperoxidase (MPO) as a marker of neutrophil influx, neutrophil elastase activity and its natural inhibitors, α1AT and secretory leukoprotease inhibitor (SLPI). Finally serum α1AT was measured to determine the degree of protein leakage (sputum sol serum α1AT ratio). Compared to current smokers, the exsmokers had a lower concentration of the chemoattractant IL‐8 (p<0.05) and a lower MPO concentration, although this failed to reach conventional statistical significance (p=0.06). Patients with α1AT deficiency had greater inflammation in the larger airways with increased LTB4 (p<0.005), MPO (p<0.001), neutrophil elastase activity (p<0.01), protein leak (p<0.001), and were found to have a lower anti‐proteinase screen with both reduced sputum α1AT (p<0.001) and SLPI concentrations (p<0.05). The reduction in sputum interleukin‐8 levels in exsmokers may decrease neutrophil influx and thus explain the slower rate of neutrophil mediated progression of lung disease compared to subjects who continue to smoke. Patients with α1‐antitrypsin deficiency had greater inflammation suggesting that α1‐antitrypsin plays an important role in protecting the larger airways from the inflammatory effects of elastase activity and may explain their more rapid progression of disease.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency

Hill¹,

Bayley²,

Campbell³

et al. 2000

Eur Respir J

104

View full text Add to dashboard Cite

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“…LTB 4 is a potent PMN chemoattractant and stimulates PMN to release elastase and generate superoxide radicals [5,36,47]. The role of LTB 4 in promoting self-perpetuating inflammatory injury at various mucosal surfaces is well established [17,19,41]. Although PMN are the principal source of LTB 4 in the bovine lung infected with M. haemolytica [8,18] the direct effects of tilmicosin on LTB 4 synthesis by bovine PMN remain incompletely understood.…”

Section: In Pmnmentioning

confidence: 99%

Tilmicosin-induced bovine neutrophil apoptosis is cell-specific and downregulates spontaneous LTB4 synthesis without increasing Fas expression

et al. 2004

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-The pathology of bacterial pneumonia, such as seen in the bovine lung infected with Mannheimia haemolytica, is due to pathogen virulence factors and to inflammation initiated by the host. Tilmicosin is a macrolide effective in treating bacterial pneumonia and recent findings suggest that this antibiotic may provide anti-inflammatory benefits by inducing polymorphonuclear neutrophilic leukocyte (PMN) apoptosis. Using an in vitro bovine system, we examined the cellspecificity of tilmicosin, characterized the changes in spontaneous leukotriene B 4 (LTB 4 ) synthesis by PMN exposed to the macrolide, and assessed its effects on PMN Fas expression. Previous findings demonstrated that tilmicosin is able to induce PMN apoptosis. These results were confirmed in this study by the Annexin-V staining of externalized phosphatidylserine and the analysis with flow cytometry. The cell-specificity of tilmicosin was assessed by quantification of apoptosis in bovine PMN, mononuclear leukocytes, monocyte-derived macrophages, endothelial cells, epithelial cells, and fibroblasts cultured with the macrolide. The effect of tilmicosin on spontaneous LTB 4 production by PMN was evaluated via an enzyme-linked immunosorbent assay. Finally, the mechanisms of tilmicosin-induced PMN apoptosis were examined by assessing the effects of tilmicosin on surface Fas expression on PMN. Tilmicosin-induced apoptosis was found to be at least partially cell-specific, as PMN were the only cell type tested to die via apoptosis in response to incubation with tilmicosin. PMN incubated with tilmicosin under conditions that induce apoptosis spontaneously produced less LTB 4 , but did not exhibit altered Fas expression. In conclusion, tilmicosin-induced apoptosis is specific to PMN, inhibits spontaneous LTB 4 production, and occurs through a pathway independent of Fas upregulation. macrolide / neutrophil / apoptosis / pasteurellosis / inflammation

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“…Furthermore, because NE can stimulate the release of cathepsin B and matrix metalloprotease-2 from macrophages [ 119 ], this can exacerbate lung damage as the resulting degradation products are found to have a chemotactic effect for monocytes [ 120 ]. NE also upregulates the release of chemotactic mediators such as leukotriene B4 [ 121 ] and IL-8 [ 122 ], which leads to an increased concentration of neutrophils in the bronchoalveolar lavage (BAL) of AATD patients [ 40 , 42 , 97 , 123 ]. Thus, the extracellular protease-antiprotease imbalance triggers a cascade of proteostasis mismanaged destruction of alveolar wall that causes defective alveoli (Fig.…”

Section: Aatd Proteostasis and Lung Diseasementioning

confidence: 99%

Managing the Adaptive Proteostatic Landscape: Restoring Resilience in Alpha-1 Antitrypsin Deficiency

Wang

Balch

2016

Alpha-1 Antitrypsin

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Neutrophil accumulation in the lung in alpha 1-antitrypsin deficiency. Spontaneous release of leukotriene B4 by alveolar macrophages.

Abstract: The emphysema of al-antitrypsin (alAT) deficiency is concep-

Cited by 189 publications

References 60 publications

Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency

Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency

Tilmicosin-induced bovine neutrophil apoptosis is cell-specific and downregulates spontaneous LTB4 synthesis without increasing Fas expression

Managing the Adaptive Proteostatic Landscape: Restoring Resilience in Alpha-1 Antitrypsin Deficiency

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