Exposure to hypoxia, leading to hypoxic pulmonary hypertension (HPH), is associated with activation of alveolar macrophages (AM). However, it remains unclear how AM participate in this process. There are studies which imply that the AM product monocyte chemoattractant protein-1 (MCP-1) plays an important role. Thus we tested: 1. if the selective elimination of AM attenuates HPH in rats, 2. the correlation of MCP-1 plasmatic concentrations with the presence and absence of AM during exposure to hypoxia, 3. the direct influence of hypoxia on MCP-1 production in isolated AM. We found that experimental depletion of AM attenuated the chronic hypoxia-induced increase in mean pulmonary arterial pressure, but did not affect the serum MCP-1 concentrations. Furthermore, the MCP-1 production by AM in vitro was unaffected by hypoxia. Thus we conclude that AM play a significant role in the mechanism of HPH, but MCP-1 release from these cells is most likely not involved in this process. The increase of MCP-1 accompanying the development of HPH probably originates from other sources than AM.
- MeSH
- alveolární makrofágy sekrece MeSH
- chemokin CCL2 krev MeSH
- dichlormethylendifosfonát terapeutické užití MeSH
- hypoxie komplikace MeSH
- plicní hypertenze imunologie prevence a kontrola MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Lungs retrieved from non-heart-beating donors (NHBDs) may alleviate the shortage of suitable organs for transplantation. The critical point is the preservation of lungs during warm ischemia, when severe damage is caused by free radicals. We investigated the effect of ventilation, pre-arrest administration of heparin, and the cell-permeable free radical scavenger, tempol, on the function of NHBD grafts. METHODS: Six experimental and two control groups (n = 6 per group) were established. All experimental groups underwent a protocol of NHBD lung harvesting, which included 1 hour of warm ischemia after pentobarbital euthanasia followed by 90 minutes of cold ischemia. The groups were constructed as follows: Group An-non-ventilated during warm ischemia, no heparin; Group Av-room-air ventilated during warm ischemia, no heparin; Group Hn-non-ventilated, heparin added pre-arrest; Group Hv-ventilated, heparin; Group Tn-non-ventilated, heparin and tempol added pre-arrest; Group Tv-ventilated, tempol, heparin; Group Ac-control group, no warm and cold ischemia, lungs harvested immediately after euthanasia; and Group Tc-controls with tempol added pre-arrest. The lungs were then perfused ex vivo and the perfusion pressure, lung weight and arteriovenous difference in oxygen partial pressure were measured. RESULTS: We found that room-air ventilation during warm ischemia caused severe pulmonary edema during reperfusion. Heparinization prevented an increase in perfusion pressure and ameliorated the oxygen transport ability. Pre-arrest administration of tempol prevented edema formation after ventilation during warm ischemia and had a positive effect on the oxygen transport ability of the lungs. CONCLUSIONS: The free radical scavenger tempol, which has a very good ability to permeate biologic membranes, contributes to better preservation of lungs retrieved from NHBDs.
- MeSH
- antikoagulancia farmakologie MeSH
- časové faktory MeSH
- cyklické N-oxidy farmakologie MeSH
- dárci tkání MeSH
- financování organizované MeSH
- heparin MeSH
- krysa rodu rattus MeSH
- plíce fyziologie účinky léků MeSH
- plicní ventilace MeSH
- reperfuzní poškození prevence a kontrola MeSH
- scavengery volných radikálů farmakologie MeSH
- spinové značení MeSH
- srdeční zástava MeSH
- teplá ischemie škodlivé účinky MeSH
- transplantace plic MeSH
- uchovávání orgánů metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
BACKGROUND: Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. Vascular remodeling is associated with collagenolysis and activation of matrix metalloproteinases (MMPs). One of the possible sources of MMPs in hypoxic lung are mast cells. OBJECTIVE: The role of lung mast cell collagenolytic activity in hypoxic pulmonary hypertension was tested by the inhibitor of mast cell degranulation disodium cromoglycate (DSCG). METHODS: Rats were treated with DSCG in an early or later phase of isobaric hypoxia. Control groups were exposed to hypoxia only or to normoxia. Lung hemodynamics, muscularization and collagen metabolism in the walls of peripheral pulmonary vessels in the lungs were measured. RESULTS: DSCG applied at an early phase of exposure to hypoxia reduced the development of pulmonary hypertension, inhibited muscularization in peripheral pulmonary arteries and decreased the amount of collagen cleavage fragments in prealveolar vessels. CONCLUSIONS: Mast cell degranulation plays a role in the initiation of hypoxic pulmonary vascular remodeling. 2008 S. Karger AG, Basel.
- MeSH
- arteria pulmonalis metabolismus MeSH
- degranulace buněk účinky léků MeSH
- financování organizované MeSH
- hypoxie komplikace MeSH
- kolagen metabolismus MeSH
- kromoglykát dvojsodný farmakologie MeSH
- krysa rodu rattus MeSH
- mastocyty fyziologie účinky léků MeSH
- plicní hypertenze etiologie metabolismus patofyziologie prevence a kontrola MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- MeSH
- financování vládou MeSH
- Publikační typ
- abstrakty MeSH
Pathogenesis of hypoxic pulmonary hypertension is initiated by oxidative injury to the pulmonary vascular wall. Because nitric oxide (NO) can contribute to oxidative stress and because the inducible isoform of NO synthase (iNOS) is often upregulated in association with tissue injury, we hypothesized that iNOS-derived NO participates in the pulmonary vascular wall injury at the onset of hypoxic pulmonary hypertension. An effective and selective dose of an iNOS inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL), for chronic peroral treatment was first determined (8 mg/l in drinking water) by measuring exhaled NO concentration and systemic arterial pressure after LPS injection under ketamine+xylazine anesthesia. A separate batch of rats was then exposed to hypoxia (10% O2) and given L-NIL or a nonselective inhibitor of all NO synthases, N(G)-nitro-L-arginine methyl ester (L-NAME, 500 mg/l), in drinking water. Both inhibitors, applied just before and during 1-wk hypoxia, equally reduced pulmonary arterial pressure (PAP) measured under ketamine+xylazine anesthesia. If hypoxia continued for 2 more wk after L-NIL treatment was discontinued, PAP was still lower than in untreated hypoxic controls. Immunostaining of lung vessels showed negligible iNOS presence in control rats, striking iNOS expression after 4 days of hypoxia, and return of iNOS immunostaining toward normally low levels after 20 days of hypoxia. Lung NO production, measured as NO concentration in exhaled air, was markedly elevated as early as on the first day of hypoxia. We conclude that transient iNOS induction in the pulmonary vascular wall at the beginning of chronic hypoxia participates in the pathogenesis of pulmonary hypertension.
- MeSH
- aplikace orální MeSH
- arteria pulmonalis enzymologie MeSH
- časové faktory MeSH
- chronická nemoc MeSH
- financování organizované MeSH
- hypoxie MeSH
- inhibitory enzymů aplikace a dávkování farmakologie MeSH
- krysa rodu rattus MeSH
- lysin aplikace a dávkování farmakologie MeSH
- NG-nitroargininmethylester farmakologie MeSH
- oxid dusnatý MeSH
- plíce metabolismus MeSH
- plicní hypertenze etiologie patofyziologie MeSH
- potkani Wistar MeSH
- synthasa oxidu dusnatého, typ II antagonisté a inhibitory biosyntéza MeSH
- vydechnutí MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- O autorovi
- Herget, Jan, 1945-2019 Autorita
