Stress, glucocorticoids and ageing of the immune system

Stress,glucocorticoids and ageing of the immune system

MOISE

′S EVANDRO BAUER Instituto de Pesquisas Biome

′dicas and Faculdade de Biocie ?ncias,Pontif?′cia Universidade Cato ′lica do Rio Grande do Sul,Porto Alegre,Brazil

(Received 1October 2004;revised 8March 2005;accepted 10March 2005)

Abstract

Ageing has been associated with immunological changes (immunosenescence)that resemble those observed following chronic stress or glucocorticoid (GC)treatment.These changes include thymic involution,lower number of na?¨ve T cells,reduced cell-mediated immunity,and poor vaccination response to new antigens.It follows that immunosenescence could be associated with changes of peripheral GC levels.Indeed,when compared with young subjects,healthy elders are more stressed and show activation of the hypothalamus–pituitary–adrenal (HPA)axis.However,both bene?cial and undesirable effects of GCs ultimately depend on the target tissue sensitivity to these steroids.Recent data indicate that peripheral lymphocytes from elders respond poorly to GC treatment in vitro .The present review summarizes recent ?ndings which suggest that immunosenescence may be closely related to both psychological distress and stress hormones.Furthermore,chronically stressed elderly subjects may be particularly at risk of stress-related pathology because of further alterations in GC-immune signalling.Finally,the neuroendocrine hypothesis of immunosenescence is ?nally reconsidered in which the age-related increase in the cortisol/DHEA ratio is major determinant of immunological changes observed during ageing.

Keywords:Hypothalamo–pituitary–adrenal axis,aging,psychological stress,glucocorticoids,lymphocytes

Introduction

Ageing is a continuous and slow process that

compromises the normal functioning of various organs

and systems in both qualitative and quantitative terms

(Malaguarnera et al.2000).The immune system is not

an exception and immunological changes observed

during ageing are collectively known as immunosene-

scence.Although some immunological parameters are

known to deteriorate,others remain unchanged or

even increase during ageing.For instance,the innate

immune system (e.g.macrophages and neutrophils)

seems to be preserved during ageing in contrast to

several age-related decrements in adaptive immune

responses,especially those regulated by T cells

(Pawelec et al.2002).It remains controversial whether

these changes cause or are caused by underlying

disease commonly observed in elderly populations.Therefore,strenuous efforts have been made to circumvent this problem by separating “disease”from “ageing”,as exempli?ed by the application of the SENIEUR protocol (Ligthart et al.1984),which de?nes rigorous criteria for selecting healthy individ-uals in immunogerontological studies.The health state is checked according to clinical investigations and to haematological and various biochemical parameters.The exclusion criteria include:infections,acute or chronic in?ammation,autoimmune diseases,heart disease,under-nourishment,anaemia,leucopenia,clinical depression,neurodegenerative disease,neo-plasia and use of hormones and drugs.When diseased subjects are excluded,immunosenescence involves thymic involution,lower lymphocyte counts (e.g.na?¨ve T cells),switch from Th1to Th2cytokines,impaired humoral responses to new antigens and blunted T -cell

ISSN 1025-3890print/ISSN 1607-8888online q 2005T aylor &Francis Group Ltd

DOI:

10.1080/10253890500100240

Correspondence:M.E.Bauer,Laboratory of Cellular and Molecular Immunology,Instituto de Pesquisas Biome

′dicas,Hospital Sa ?o Lucas–PUCRS,Av.Ipiranga 6690,28andar–PO Box 1429.90.Porto Alegre,RS 610-000,Brazil.T el:555133203000/Ext.2725.Fax:555133203312.E-mail:mebauer@pucrs.br

Stress ,March 2005;8(1):69–83

proliferation(reviewed in Pawelec et al.2002). The clinical consequences of immunosenescence may include increased susceptibility to infectious diseases,neoplasias and autoimmune diseases (Castle2000).However,this altered morbidity is not evenly distributed and may be in?uenced by other immune-modulating factors.Other factors may thus potentially contribute to the heterogeneity of these changes,including psychoneuroendocrine systems.Indeed,several immunosenescence-related changes(e.g.thymic involution,lower counts of na?¨ve T cells and blunted T-cell proliferation)resemble those observed following chronic stress(Selye 1936,McEwen et al.1997)or glucocorticoid(GC) treatment(Fauci1975).

The hypothalamus–pituitary–adrenal(HPA)axis is pivotal for the homeostasis of the immune system and its dysregulation has been associated with several immune-mediated diseases.For instance,HPA axis over-activation,as occured during chronic stress,can affect susceptibility to,or severity of infectious disease through the immunosuppressive effect of the GC (Kiecolt-Glaser et al.1996,Vedhara et al.1999). In contrast,blunted HPA axis responses are associated with enhanced susceptibility to auto-immune in?ammatory disease(Sternberg2002). However,there are some discrepancies compared with the original?ndings of Sternberg and some groups have failed to demonstrate the relationship between corticosterone responses and susceptibility/ severity to in?ammatory disease(Harbuz et al.1993). For instance,a number of laboratories have failed to replicate the difference in stress response between the Lewis and Fischer strains of rats(Dhabhar et al. 1993,Rivest and Rivier1994).It is noteworthy that elderly subjects are particularly at risk for both infectious and chronic in?ammatory diseases. Furthermore,chronic in?ammatory diseases may be associated with premature ageing of the immune system and present several similarities of immunosenescence including shortening of telomeres,decreased T-cell receptor speci?cities, loss of na?¨ve T cells and increased production of pro-in?ammatory cytokines(Straub et al.2003). Dysregulation of the HPA axis may contribute,but it is not solely responsible for immunosenescence. Chronically stressed elderly subjects may be at risk of stress-related pathology because of further altera-tions in GC immunoregulation(immune signalling). The present review summarizes recent?ndings which suggest that immunosenescence may be closely related to both psychological distress and stress hormones.In particular,striking similarities in immunological changes are found during ageing, stress exposure or GC treatment in vivo.Finally,the neuroendocrine hypothesis of immunosenescence is reconsidered,in which the age-related increase in the cortisol/DHEA ratio is considered to be a major determinant of immunological changes observed during ageing.

Healthy ageing is associated with a psychoneuro-endocrine activation

Psychological status may be an important risk factor for immunosenescence.Human ageing has been associated with several psychological and behavioural changes,including dif?culty in concentrating, progressive cognitive impairments and sleep disturb-ances(Howieson et al.2003,Piani et al.2004). Although individually identi?ed,these alterations may be associated with major depression.Indeed, depression is highly prevalent in several age-related chronic degenerative diseases,including cardiovascu-lar diseases,Parkinson’s disease,Alzheimer’s demen-tia,cancer and rheumatoid arthritis(Dew et al.1998). In addition,both aging(Gabriel et al.2002)and major depression(Trzonkowski et al.2004,Schiepers et al. 2005)have been associated with increased levels of pro-in?ammatory cytokines and could thus contribute to further immunological diseases in the frail elderly. We have recently demonstrated that healthy ageing is associated with signi?cant psychological distress. In particular,it was found that SENIEUR elders were signi?cantly more stressed,anxious and depressed than young adults(Luz et al.2003,Collaziol et al.2004).It is noteworthy to mention here,however, that the elderly subjects investigated in this study were not suffering from clinical depression or chronic stress. In fact,all were non-institutionalized and socially active individuals.Several stressors were ascribed to the healthy elders,including:feeling unable to work or having problems with performing their house work, sexual problems and reduced libido,loss of a relative or friend,and social exclusion.The literature regarding age-related psychological changes is controversial and others did not?nd these changes(Nolen-Hoeksema and Ahrens2002).This could be due to methodologi-cal issues,since speci?c clinical interviews are required to assess depression in the elderly.

Ageing of the endocrine system(endocrinosene-scence)may be another risk factor for immunosene-scence.Endocrinosenescence can be demonstrated by a substantial decline in secretion of several hormones, including growth hormone(GH),testosterone,pro-gesterone,aldosterone and dehydroepiandrosterone (DHEA).DHEA and its sulphated metabolite (DHEAS)are hormones secreted by the adrenal cortex in response to adrenocorticotropin(ACTH). DHEA production follows a circadian pattern,with peak levels in the morning and lower levels in the evening.Serum DHEA levels decrease by the second decade of life reaching about5%of the original level in the elderly(Migeon et al.1957).We have recently demonstrated that SENIEUR elders had signi?cantly lower serum(Luz et al.2003),as well as salivary,

M.E.Bauer 70

DHEA levels throughout the day compared to young

adults (254%in the morning;Figure 1B).In addition

to blunted hormonal production,the elderly subjects

also showed a ?at circadian pattern for DHEA

secretion.The morphological correlate of the age-

related changes in DHEAS/DHEA secretion is

progressive atrophy of the zona reticularis of the

adrenal glands (Ferrari et al.2001).

DHEA and its sulphated form have been reported

to have immunomodulatory properties,including

increased mitogen-stimulated IL-2production

(Daynes et al.1990,Suzuki et al.1991),diminished

TNF-a or IL-6production (Di Santo et al.1996,

Straub et al.1998),inhibition of natural killer cell

differentiation (Risdon et al.1991)or rodent mitogen-

induced lymphocyte proliferation (Padgett and Loria

1994).Furthermore,DHEA has been proposed to

exert restoring effects on immunosenescence,includ-

ing an important adjuvant effect on the immunization

of aged mice with recombinant hepatitis B surface

antigen (Araneo et al.1993)or in?uenza (Danenberg

et al.1995).It could be thus speculated that a lack of

DHEA in peripheral tissues during ageing would

further deteriorate immune responses and may be

another contributing factor for immunosenescence.

However,DHEA treatment did not produce any

bene?cial effect on the immune response to in?uenza vaccination in elderly subjects (Danenberg et al.1997).Therefore,extrapolation from studies on murine models to the human should be regarded with caution.There is also evidence suggesting that ageing is associated with signi?cant activation of the HPA axis (Halbreich et al.1984,Van Cauter et al.1996,Deuschle et al.1997,Heuser et al.1998,Ferrari et al.2000,Ferrari et al.2004),resulting in increased production of ACTH and cortisol,as well as catecholamines through activation of the sympath-etic-adrenal medullary system,that modulate several immune responses (Munck et al.1984).Indeed,we have recently demonstrated that SENIEUR elders had signi?cantly higher (,45%)salivary cortisol pro-duction throughout the day compared to young adults (Figure 1A)(Luz et al.2003).Salivary cortisol level peaked in the morning and presented a nadir at night,with a regular circadian pattern for both groups.These results are in contrast with previous studies that have demonstrated a ?attened diurnal amplitude of ACTH and cortisol levels during ageing (Deuschle et al.1997,Ferrari et al.2004).Another way to evaluate adrenocortical function is through assessment of the molar concentrations of adrenal hormones (Straub et al.2000,Ferrari et al.2001,Butcher and Lord 2004).We

have

Figure 1.The production of adrenal hormones during healthy ageing.Saliva samples were collected from healthy elders (n ?46;31females;aged from 60–91years;mean age ?72.00^8.51years)and young adults (n ?33;18females;aged from 20–40years;mean age ?27.40^6.70years)and hormones were detected by RIAs.The mean (^SEM)salivary levels of cortisol (A),DHEA (B)and the molar cortisol/DHEA ratio (C)at each time point are shown.Statistically signi?cant differences are indicated:*p ,0:05;***p ,0:0001(repeated measures ANOVA,multiple comparisons made with Tukey’s test).The study protocol was approved by both scienti?c and ethics committees of PUCRS.

Stress and ageing of the immune system 71

demonstrated that SENIEUR elders had signi?cantly increased molar cortisol/DHEA ratio at all time points compared to young adults(Figure1C).The cortisol/ DHEA ratio may be more informative than isolated values of cortisol and DHEA and it may indicate that high cortisol and low(serum)DHEA levels in ageing are contributory to a cytotoxic action in the brain. The antagonist action of DHEA on cortisol actions in the brain suggests that measurement of cortisol alone may provide an incomplete estimate of hypercortisolemia.

Increased cortisol levels are also seen in demented patients(Maeda et al.1991),major depression(Gold et al.1988)or during chronic stress(Kirschbaum et al. 1995,Bauer et al.2000).In our previous study, psychological distress was positively related to salivary cortisol levels and negatively correlated to DHEA levels during ageing(Luz et al.2003).Therefore,it becomes dif?cult to dissociate these neuroendocrine changes observed in the elderly with those produced by psychological stimuli.

The glucocorticoid cascade hypothesis

Cumulative neural damage produced by stressors during life may contribute to increased HPA function during ageing.In this context,peripheral GCs may have an important role in damaging key brain areas involved with regulation of the HPA axis.Evidence for GC involvement in hippocampal ageing led to the establishment of the“glucocorticoid cascade hypo-thesis”(Sapolsky et al.1986).This hypothesis states that GCs participate in a feed-forward cascade of effects on the brain and body.In this case,progressive damage to the hippocampus,induced by GCs, promotes a progressive elevation of adrenal steroids (i.e.cortisol)and dysregulation(down regulation of GC receptors)of the HPA axis(Sapolsky et al.1986). The glucocorticoid cascade hypothesis of ageing is a prime example of“allostatic load”(McEwen1998, McEwen2003)since it recognizes a mechanism that gradually wears down a key brain structure,the hippocampus,while the gradually dysregulated HPA axis promotes pathophysiology in tissues and organs throughout the body.The net results of the age-related hippocampal damage are impairment of episodic,declarative,spatial,and contextual memory and also in the regulation of autonomic,neuroendo-crine,and immune responses.It should be mentioned that the effects of GCs on the hippocampus are reversible.Sapolsky et al.(1986)have also proposed that several age-related pathologies are also observed following excessive GC exposure and include muscle atrophy(Salehian and Kejriwal1999),osteoporosis/ hypercalcemia(T amura et al.2004),hyperglycemia/ hyperlipidemia,atherosclerosis,type II diabetes and major depression(Lee et al.2002,Juruena et al.2003).Immunosenescence:Age or stress-related?

We have now discussed that healthy ageing is associated with psychological distress in parallel with a signi?cant activation of the HPA axis.However,it remains controversial whether cortisol changes cause or are caused by age-related psychological distress.All immune cells exhibit receptors for the neuroendocrine products of the HPA and sympathetic-adrenal medullary axes.It seems reasonable to speculate that increased cortisol and reduced DHEA secretion may thus contribute to immunological changes observed during ageing.Indeed,several immunosenescence-related changes(e.g.thymic involution,lower counts of na?¨ve T cells and blunted T-cell proliferation)are identical to those observed following chronic stress (Selye1936,McEwen et al.1997)or GC treatment (Fauci1975,Bauer et al.2002).This section will outline the similarities of immunological changes found during ageing,stress or GC treatment in vivo. Changes in cellular traf?cking

Traf?cking or redistribution of peripheral immune cells in the body is of paramount importance for effective cell-mediated immune responses.Ageing is associated with several peripheral quantitative changes in leukocytes,including a decrease of na?¨ve(CD45RAt)and an increase of memory (CD45ROt)T cells,an expansion of CD28-T cells or an increase of natural killer(NK)cells(Hannet et al. 1992,Gabriel et al.1993,Globerson and Effros2000, Martinez-Taboada et al.2002).Overall,cellular components of the innate immune system(e.g. monocytes,neutrophils and NK cells)seem to be preserved during ageing in contrast to several age-related decrements in adaptive immune responses–especially T cells(Pawelec et al.2002).However, T cells are also especially targeted during chronic stress exposure(Biondi2001)or following GC treatment in vivo(McEwen et al.1997,Bauer et al. 2002)(see T able I).In spite of the several similarities among age-and stress-related immunological altera-tions,only a few studies have addressed the role of stress factors on human immunosenescence.

We have recently investigated the role of psycho-neuroendocrine factors in regulating the distribution of peripheral T-cell subsets during healthy ageing (Collaziol et al.2004).The mechanisms underlying the regulation of the peripheral pool of lymphocytes are still largely unknown.It has been speculated that CD95(APO1/Fas)may be involved in this process through engagement of apoptosis(Potestio et al. 1999).CD95is a member of the tumour necrosis factor(TNF)family and its ligand(CD95L)is found on activated T cells(Nagata and Golstein1995). CD95-CD95L binding seems to play an important role in maintaining the cellular homeostasis of

M.E.Bauer 72

the immune system and may contribute to stress-related changes in cell traf?cking(Yin et al.2000). Con?rming previous reports,we recently demon-strated that changes in lymphocyte distribution were noted in the elderly as demonstrated by a signi?cant decrease in na?¨ve T cells associated with higher expression of CD95in this subset(Collaziol et al. 2004).We have speculated that this differential expression of CD95may potentially select na?¨ve T cells for apoptosis and could further explain age-related reductions in CD45RAtcells.Furthermore, healthy elders were signi?cantly distressed and stress scores were found positively associated to CD95 expression on CD45RAtcells.

GC may also contribute to the quantitative cellular changes observed during ageing.It has been demon-strated that GC-induced apoptosis on monocytes is at least partially mediated by the expression of both CD95and CD95L(Schmidt et al.2001).Another study showed that GCs may either induce T-cell apoptosis in a CD95-independent manner,or protect T cells from CD95-mediated apoptosis(Zipp et al. 2000).Furthermore,there is some evidence that psychological stress may regulate the proportion of peripheral lymphocytes via the expression of CD95.It has been demonstrated that chronic stress may induce lymphocyte apoptosis in mice(Yin et al.2000)or in man(Oka et al.1996)via upregulation of CD95.Our results support the concept that age-or stress-related increase in cortisol levels may be preferentially altering the expression of CD95on CD45RAtcells. Preliminary data from our laboratory indicate that human CD45RAtCD95tcells are in fact more sensitive to dexamethasone(DEX)treatment in vitro (unpublished results).There are some data suggesting that human na?¨ve T CD4tcells are more sensitive to DEX than memory T CD4tcells(Nijhuis et al. 1995).Overall,our results suggest that there are complex psychoneuroendocrine interactions involved with the regulation of the peripheral pool of lymphocytes.In particular,it was shown that both psychological stress and GCs synergise during ageing to produce alterations in T-cell traf?cking.

Changes in cell-mediated immunity

Cell-mediated immunity is a process that requires(1) recognition of antigens,(2)cell activation and pro-liferation,and(3)effector functions such as cellular cytotoxicity,phagocytosis and immunoglobulin syn-thesis.Steps2and3seem to be particularly impaired during ageing.Following antigen recognition, lymphocytes need to divide into several clones in order to mount effective cell-mediated immune responses.Cell division or proliferation can be readily assessed in vitro by stimulating lymphocytes with mitogens.When diseased subjects are excluded, immunosenescence involves impaired humoral responses and blunted T-cell proliferation to mitogens (Pawelec et al.2002).The latter is one of the most documented age-related change observed during ageing(Murasko et al.1987,Liu et al.1997).Y et, these changes are not exclusive to ageing,and stress or GC treatments are also associated with decrements in T-cell proliferation(Sapolsky et al.2000,Biondi 2001)(see Table II).Indeed,we have recently observed that healthy elders were signi?cantly more distressed,had an activated HPA axis and had signi?cant lower(253.6%)T-cell proliferation com-pared to young adults(Luz et al.2002)(Figure2). Interestingly,the HPA axis may be implicated in this change since salivary cortisol levels were found to be negatively correlated with T-cell proliferation (data not shown).

Thymic involution is a common consequence of mammalian ageing and it precedes the malfunctioning of the immune system,resulting in a diminished capacity to generate new T-cells.This thymic involution has been proposed to be due to changes in the thymic microenvironment resulting in its failure to support thymopoiesis(Henson et al.2004). However,stress-related GCs(Selye1936)or GC

T able https://www.wendangku.net/doc/9517901939.html,parison of changes in cellular traf?cking.

Cell Ageing Stress GC treatment

Neutrophils,**

Monocytes,+,

NK cells***

B cells+++

CD4tT cells+++

CD8tT cells++or*+

CD3tCD45RAt+++

CD3tCD45ROt*+or*+

CD3tCD28-*??

Direction of arrows indicate increase(*),decrease(+)or no

change(,)compared to corresponding control levels.??data not

available;NK,natural killer;CD3tCD45RAt,na?¨ve T cells;

CD3tCD45ROt,memory T cells.Based on data in:(Fauci,1975,

McEwen et al.1997,Globerson and Effros,2000,Biondi,2001,

Bauer et al.2002).

T able https://www.wendangku.net/doc/9517901939.html,parison of changes in cell-mediated immunity.

Mechanism Ageing Stress GC treatment

Thymus+++

T-cell proliferation+++

Cytotoxicity+++

IL-2,IFN-g+++

IL-4,IL-10***

TNF-a,IL-1,IL-6*or,*+

Direction of arrows indicate increase(*),decrease(+)or no

change(,)compared to corresponding control levels.Based on

data in:Ramirez et al.1996,Globerson and Effros,2000,Sapolsky

et al.2000,Biondi,2001,Galon et al.2002.

Stress and ageing of the immune system73

treatment (Fauci 1975)also atrophy the thymus

and,to a lesser extent,other lymphoid tissues,

triggering apoptotic death in immature T and B cell

precursors and mature T cells (Sapolsky et al.2000).

Therefore,thymic involution is not a phenomenon

exclusive to ageing.

The effector phases of both innate and acquired

immunity are in large part mediated by cytokines.

Different subpopulations of CD4tT cells synthesize

speci?c cytokines and have been designated Th1

(IFN-g ,IL-2,lymphotoxin a )or Th2(IL-4,IL-10)

cells.Th1cytokines provide help for cell-mediated

responses and the IgG2a antibody class switching,

whereas Th2cytokines help B cells and IgA,IgE and

IgG1antibody class switching.Both human and

mouse models have demonstrated that ageing is

associated with a Th1to Th2shift in cytokine

production (Globerson and Effros 2000,Ginaldi et al.

2001).However,this is not an age-speci?c pheno-

menon but is also seen during stress (Biondi 2001,

Glaser et al.2001)or GC treatment (Ramirez et al.

1996,Galon et al.2002).

Recent work suggests that cytokines and hormones

could be considered as possible links between

endocrinosenescence and immunosenescence

(Straub et al.2000).Indeed,it has long been known

that pro-in?ammatory cytokines can readily activate

the HPA axis during infection in animals (Besedovsky

et al.1977)or after administration in humans

(Mastorakos et al.1993).Other studies have

linked the age-related decline in DHEA production to increased serum levels of IL-6(Daynes et al.1993,Straub et al.1998).In addition,increased plasma TNF-a levels were correlated to major depression in the elderly (Vetta et al.2001).However,we do not know exactly how the extent of these changes may be related to altered psychological and HPA axis functions in the elderly.We have recently investigated whether psycho-neuroendocrine status of healthy elders was associated with changes in lipopolysaccharide (LPS)-induced monocyte production of pro-in?ammatory cytokines (TNF-a and IL-6)and soluble IL-2receptor (sIL-2R a )production by T cells in vitro (Luz et al.2003).Cells of healthy elders produced equivalent pro-in?ammatory cytokines and soluble IL-2R a when compared to cells of young adults.These data are in disagreement with previous work showing that human ageing was associated with increased serum (Straub et al.1998)or monocyte pro-in?ammatory cytokine levels (Fagiolo et al.1993,Gabriel et al.2002).However,these data should be interpreted with caution because other cellular sources than monocytes can produce cytokines and thus increase serum levels.Considering that our cohort of elderly subjects was signi?cantly distressed,we hypothesize this could have normalised the cytokines investigated in this study–due to anti-in?ammatory GC actions.On the other hand,there is also some evidence of increased pro-in?ammatory cytokine production during major depression (Vetta et al.2001,Trzonkowski et al.2004,Schiepers et al.2005).Therefore,it becomes dif?cult to dissociate the cytokine changes observed in the elderly from those induced by psychological stimuli.Ghrelin,an endogenous ligand of the GH secretagogue receptor,has been recently demonstrated to inhibit the expression and production of pro-in?ammatory cytokines (TNF-a ,IL-1b and IL-6)(Dixit et al.2004).This effect was mediated via binding on ghrelin receptors expressed on peripheral T cells and monocytes.There is some evidence for increased stomach ghrelin production in the aged rat (Englander et al.2004).Increased peripheral ghrelin levels may thus attenuate cytokine levels during ageing.It remains to be investigated,however,whether psychological stress is capable of producing signi?cant effects on stomach or immunoreactive ghrelin levels.Previous studies have long demonstrated that serum growth hormone (hGH)levels are signi?cantly reduced during ageing (Corpas et al.1993)—a process known as somatosenescence.However,hGH is not exclusively produced by the pituitary gland and human immune cells are able to secrete several neuropeptides including GH (Weigent et al.1988,Hattori et al.1994).Immunoreactive GH has several immuno-enhancing properties and may be important in modulating both humoral and cellular immune function (Weigent et al.1988,Malarkey et al.2002).However,there are no data on the impact

of

Figure 2.Healthy aging is associated with blunted T -cell

proliferation.Peripheral blood monocytes (PBMCs)were isolated

from healthy elders (n ?46;31females;aged from 60–91years;

mean age ?72.00^8.51years)and young adults (n ?33;18

females;aged from 20–40years;mean age ?27.40^6.70years)

and stimulated with phytohemagglutinin (PHA)for 96h.

Proliferation was estimated by colorimetric assays (MTT).

Proliferation/viability is expressed as optical density (OD)of

stimulated–OD of nonstimulated cultures.Statistical signi?cance

differences are indicated:***p ,0:0001(repeated measures

ANOVA,multiple comparisons were made with Tukey’s test).The

study protocol was approved by both scienti?c and ethics

committees of PUCRS.

M.E.Bauer

74

ageing on the production of GH by immune cells. In a recent study,we investigated whether somato-senescence could be associated with(a)related reduced production of immunoreactive GH and(b) psychological status of healthy SENIEUR elderly subjects(Luz et al.,submitted for publication).We found that elders(n?46;aged from60–91years; meanage?72:00^8:51years)had signi?cantly lower(77%,p?0:003;Student t test)serum hGH levels compared to young adults(n?33;aged from 20–40years;meanage?27:40^6:70years).In contrast,however,no changes in hGH production by activated monocytes or lymphocytes were observed between elders and adults.Interestingly, psychological distress(stress,anxiety and depression) was found to be negatively correlated with serum hGH levels only(r?20:27;p,0:05).No differ-ences in serum hGH levels were observed between groups when controlling for psychological variables (partial correlation).This provides the?rst line of evidence that age-related psychological distress may be implicated in somatosenescence.Finally,somato-senescence was not associated with a reciprocal decline in immunoreactive GH level.

Ageing impairs neuroendocrine-immunoregulation

Most GC effects on the immune system are mediated via intracellular GC receptors(GR;genomic action) (McEwen et al.1997).However,high concentration of GCs may also interact with membrane binding sites at the surface of the cells(nongenomic action)(Gold et al.2001).The presence of these receptors indicates that the immune system is prepared to respond to HPA axis activation and the subsequent elevation in endogenous GCs.However,the functional effect of a stress hormone will depend on the sensitivity of the target tissue for that particular hormone.For instance,the number and activity of speci?c receptors for these signalling molecules on the target organ will ultimately direct the physiologic effect of the stressor.

Recent?ndings suggest that GC sensitivity(a)may vary between different target tissues in the same organism,(b)shows large individual differences and (c)can be acutely changed in times of acute stress (Hearing et al.1999,Rohleder et al.2003). Furthermore and of special interest of this review, (d)GC sensitivity also changes during human ontogeny.Kavelaars et al.(1996)have shown that cord blood T cells of newborns appear to be extremely sensitive to inhibition of the proliferative response. This high sensitivity of cells to dexamethasone(DEX) can still be observed in the?rst two weeks after birth. Subsequently,the sensitivity to DEX inhibition of T-cell proliferation gradually decreases.At one year of age,the adult response pattern has been acquired.It is interesting that the increased sensitivity of the immune system to GC inhibition occurs at a period in life when the endogenous levels of GC are low(Sippell et al. 1978).The increased sensitivity to GC may serve as a compensatory mechanism,so that the important regulatory function of GC is fully maintained despite low circulating levels.

In a recent study,we have also investigated the lymphocyte sensitivity to both synthetic(DEX)and naturally occurring steroids(cortisol and DHEA)and so examined whether ageing was associated with alterations in neuroendocrine-immunoregulation (Luz et al.2002).We reported that healthy (SENIEUR)elders had a reduced(219%)in vitro lymphocyte sensitivity to DEX(but not cortisol or DHEA)when compared to young adults(Figure3; Fe1;72T?8:19;p?0:006;repeated measures ANOVA).This phenomenon has previously been described during chronic stress(Bauer et al.2000), major depression(Bauer et al.2002,2003)or

in Figure3.Ageing is associated with reduced lymphocyte sensitivity to GCs in vitro.PBMCs were isolated from healthy elders(n?46;31 females;aged from60–91years;mean age?72.00^8.51years)and young adults(n?33;18females;aged from20–40years;mean age?27.40^6.70years).GC sensitivity was assessed by incubating PBMCs with phytohemagglutinin(1%)and increasing concentrations of dexamethasone(A)and(B)cortisol.After96h of incubation,proliferation was estimated by colorimetric assay.Data are presented as percentage of basal proliferation(0?PHA1%without steroids).**p,0:01and*p,0:05(repeated measures ANOVA,multiple comparisons were made with Tukey’s test).The study protocol was approved by both scienti?c and ethics committees of PUCRS.

Stress and ageing of the immune system75

clinical situations where GCs are administered, including treatment of autoimmune diseases,organ transplantation,and allergies.It has been recently shown(Rohleder et al.2002)that ageing is associated with changes in GC sensitivity of pro-in?ammatory cytokine(TNF-a and IL-6)production following a psychosocial(TRIER)stress test(Kirschbaum et al. 1993).In particular,monocytes of healthy(non-SENIEUR)elderly men had a higher sensitivity to DEX treatment in vitro at baseline and showed a reduced sensitivity to this steroid following acute stress exposure(speech coupled to a mental arithmetic task). These data suggest that psychological factors may be implicated in regulating peripheral GC sensitivity during healthy ageing.

A reduced sensitivity to GCs can also be demon-strated at the central level during ageing.Indeed, higher cortisol levels in old than in young subjects have been described during some pharmacological chal-lenges,such as the DEX suppression test,and stimulation by human or ovine corticotrophin-releas-ing hormone or by physostigmine(Raskind et al. 1994,Ferrari et al.2001).

Potential mechanisms of impaired GC signalling

The mechanisms underlying acquired steroid resist-ance are poorly understood.Based on our previous observations(Luz et al.2003)we suggest that higher cortisol levels would render lymphocytes to be less sensitive to the effects of GCs in vitro.Indeed,there is some evidence in the literature suggesting that changes in GC sensitivity could be the result of chronic GC treatment(Silva et al.1994,de Kloet et al.1998). Several mechanisms may be implicated in this acquired steroid resistance(Rohleder et al.2003,Juruena et al. 2003).Figure4summarizes putative molecular mechanisms that may account for age-related changes in GC sensitivity.There is some evidence that ageing is associated with reduced numbers of intracellular GRs (Zovato et al.1996,Grasso et al.1997)but changes in GR af?nity cannot be ruled out.In addition,altered translocation of GC/GR complex to the nucleus and altered activity of transcription factors may also explain acquired GC resistance.Alternatively,it has been shown that a non-ligand binding b-isoform of the human GR(hGR b)may also be implicated in acquired steroid resistance(Castro et al.1996).It was hypothesised that the hGR b probably heterodimerises with ligand-bound hGR a and translocates into the nucleus to act as a dominant negative inhibitor of the classic receptor.However,there is no evidence for age-related changes in expression of GR isoforms. Furthermore,we cannot exclude the participation of mutations in the GR or changes in the GR transduction system(e.g.altered AP-1and NF-k B expression,heat shock proteins)in promoting tissue sensitivity to GC (reviewed in Bronnegard et al.1996).

In addition,there is considerable evidence that cytokines may have a signi?cant impact on GR expression and function.There is some evidence suggesting that local concentrations of cytokines produced during an in?ammatory response may produce acquired GR resistance(Pariante et al. 1999a).Of note for the pathogenesis of GR resistance in major depression is that this disease has been associated with increased levels of pro-in?ammatory cytokines(TNF-a,interleukin(IL)-1and IL-6)and acute phase proteins(Maes et al.1993,Trzonkowski et al.2004,Schiepers et al.2005).Furthermore,it has recently been shown that IL-13,a cytokine with similar properties to IL-4,reduces GR binding af?nity in peripheral blood mononuclear cells(PBMCs);(Spahn et al.1996).In summary,various mechanisms may mediate age-related changes in immune GC signalling, however,further research is required to fully understand the basis of the changes in altered lymphocyte sensitivity to steroid.

The impact of chronic stress on immunosenescence and health

Elderly individuals who experience chronic stress may exhibit poorer immune function and increased disease vulnerability than their less stressed counterparts. Elderly spousal caregivers of dementia patients have been adopted by several investigators as a model for exploring the impact of chronic stress on human endocrine and immune function.We have previously demonstrated that caregivers of demented patients had a blunted T-cell proliferation in association with increased cortisol levels(Bauer et al.2000)compared to non-stressed elders.Furthermore,lymphocytes of elderly caregivers were more resistant to GC treatment in vitro compared to non-caregiver elders.When stressed elderly is compared to healthy elderly and young adults(see Figure5),these immunological changes are found in similar magnitude to increased cortisol levels.These data suggest that chronic stress and cortisol would thus accelerate human immuno-senescence.Indeed,it has recently been observed that psychological stress(both perceived stress and chroni-city of stress)was signi?cantly associated with higher oxidative stress,lower telomerase activity,and shorter telomere length,which are known determinants of cell senescence and longevity(Epel et al.2004).

Several studies have implicated caregiving as a risk factor for health of elderly https://www.wendangku.net/doc/9517901939.html,pared with non-caregivers,subjects who provide care to a spouse with a stroke or dementia report more infectious illness episodes(Kiecolt-Glaser et al.1991),they have poorer immune responses to in?uenza virus(Kiecolt-Glaser et al.1996,Vedhara et al.1999)and pneumococcal pneumonia vaccines(Glaser et al.2000),they present slow wound healing(Kiecolt-Glaser et al.1995),they are at greater risk for developing mild hypertension

M.E.Bauer 76

(Shaw et al.1999),and they may be at greater risk

for coronary heart disease (Vitaliano et al.2002).

In addition,a prospective longitudinal study found that

the relative risk for mortality among caregivers was

signi?cantly higher (63%)than non-caregiving con-

trols (Schulz and Beach 1999).A recent study indicates

that a pro-in?ammatory cytokine (IL-6)may be

involved with this increased morbidity in caregiving

populations (Kiecolt-Glaser et al.2003).Overproduc-

tion of IL-6has been associated with a spectrum of age-

related conditions including cardiovascular disease,

osteoporosis,arthritis,type 2diabetes,certain cancers,

periodontal disease,frailty,and functional decline.

T o assess the impact of chronic stress on longitudinal

IL-6production,Kiecolt-Glaser et al.(2003)investigated the pattern of change in IL-6over six years among a large community of elderly caregivers for spouses with dementia and noncaregiver elders.Interestingly,caregivers’average rate of increase in IL-6level was about four times as large as that of noncaregivers.These data provide evidence of a key mechanism through which chronic stressors may accelerate risk of a host of age-related diseases by prematurely ageing the immune system.It remains to be investigated,however,how the extent of these changes may be related to neuroendocrine alterations observed during ageing.Chronic stress and GC excess have also been implicated in accelerated ageing of different mammal and non-mammal species (Butcher and Lord

2004).

Figure 4.Peripheral sensitivity to glucocorticoids is regulated by diverse tissue and cellular mechanisms.Extracellular hormone availability can be determined by ()differential tissue-dependent expression of 11b -hydroxysteroid dehydrogenases that catalyze the interconversion of active glucocorticoids (cortisol)to inactive forms (cortisone)and vice versa (Zhang et al.2005);and ()levels of plasma corticosterone binding globulin (CBG)which delivers biologically active glucocorticoids (GCs)into peripheral tissues.Intracellular sensitivity to glucocorticoids can be modulated by several mechanisms,including:()altered densities of functional membrane or intracellular glucocorticoid receptor (GR a )as well as receptor af?nity changes (Pereira et al.2003);()altered expression of heat shock proteins (HSP90and HSP56)which stabilize GR a and are dissociated following binding of GCs (Picard et al.1990);()altered expression of GR b which in turn antagonises GR a (Castro et al.1996);()altered translocation of GR-GC complexes into the nucleus (Matthews et al.2004);()altered expression of several cytokines (Kam et al.1993,Pariante et al.1999b);and ()altered expression of transcription factors AP-1(Adcock et al.1995)and NF k B which in turn antagonise GR a .Dashed lines represent inhibitory actions on GR a .

Stress and ageing of the immune system 77

For instance,GC are clearly involved with premature

ageing (programmed death)observed in spawning

salmons.In order to spawn billions of eggs in the

fresh-water stream of their birth,salmon need to leap

over dams,waterfalls and escape from predators.This

strenuous physical stress is associated with several

bodily alterations that were initially observed by

Hans Selye and termed the general adaptation

syndrome (Selye 1936).Following spawning,salmon

have huge adrenals (and intense GC production),

peptic ulcers,kidney lesions,and frail immune

systems (Robertson and Wexler 1957).The animal

generally dies of multiple infections.However,if the

adrenals are removed after spawning,the salmon will

live for over a year afterward.Programmed ageing is

not exclusive to salmon but also observed in

Australian marsupial mice (McDonald et al.1981).

According to Dr Robert Sapolsky,“if you want

to degenerate very fast,secrete a ton of GCs”

(Sapolsky 1998).

Conclusions and outlook

When age-related diseases are controlled for,healthy

ageing is associated with changes in allostatic

systems (endocrine and immune)that play major

roles in the adaptation of the organism to outside

forces that are threatening the homeostasis of the

internal milieu.In particular,healthy ageing has

been associated with signi?cant psychological dis-tress and activation of the HPA axis (increased cortisol and reduced DHEA).Over weeks,months,or years,exposure to increased secretion of stress hormones can result in allostatic load (“wear and tear”)and its pathophysiologic consequences (McE-wen 1998).Given the ?ndings that even discrete HPA axis activation may impair cognitive function (Lupien et al.1994)and induce sleep disturbances (Starkman et al.1981),conditions that are fre-quently associated in the elderly,psychological or pharmacological strategies attenuating or preventing increased HPA function during ageing might be of considerable bene?t for the elderly.The studies reviewed here support the notion that immunological changes observed during healthy ageing may be closely related to both psychological distress and stress hormones.Of note,changes in cellular traf?cking as well as cell-mediated immunity observed during ageing are similarly found following stress or chronic GC exposure.These changes are mainly produced via engagement of speci?c intra-cellular adrenal corticoid receptors expressed on peripheral lymphocytes.Based on these data,the neuroendocrine hypothesis of immunosenescence is reconsidered here (see Figure 6).During ageing,cumulative neuronal damage produced by stress-related cortisol action in the brain (hippocampus and hypothalamus)is associated with decreased central sensitivity to cortisol (Sapolsky et al.1986,Raskind et al.1994,Ferrari et al.2001).This will lead

to

Figure 5.Impact of chronic stress on cortisol and T -cell function during ageing.Y oung adults (Y),elderly (E)or stressed elderly (SE)subjects were compared according to area under the curve (AUC)cortisol production (A),T -cell proliferation response to phytohemagglutinin (PHA)stimulation (B),or T -cell sensitivity to glucocorticoids in vitro (C).Data are summarized from previous work (Bauer et al.2000,Luz et al.2002,Luz et al.2003)and shown as the percentage of change between groups.

M.E.Bauer

78

increased cortisol levels (Halbreich et al.1984,

Van Cauter et al.1996,Deuschle et al.1997,Heuser

et al.1998,Luz et al.2003,Ferrari et al.2004)which

in turn may produce more neuronal damage in the

brain and promote thymic involution.These effects

may be exacerbated by reduced DHEA/DHEAS levels

frequently observed during ageing.The impaired

DHEAS secretion,together with the increase in

cortisol,results in an enhanced exposure of various

bodily systems (including brain and immune system)

to the cytotoxic/immunomodulatory effects of GCs.

These tissues are preferentially targeted by cumulative

cortisol action because they express the greatest

densities of MRs (hippocampus)and GRs (thymus)

(McEwen et al.1997).The critical consequence of

thymic involution is reduced output of na?¨ve T cells—

a hallmark of immunosenescence.It remains to be

investigated,however,why peripheral T cells are

preferentially targeted during ageing comparing to B

or NK cells.It should be kept in mind this hypothesis

is over simplistic and does not take into account other

stress-related mediators (e.g.neuropeptides,nor-

adrenaline,GH)and intrinsic cellular mechanisms

of ageing,including oxidative stress and telomere

shortening.Further studies are required to investigate

whether cellular ageing is associated with ageing

of neuroendocrine functions.In addition,the role of

increased cortisol/DHEA ratio during immunosene-

scence may be over simplistic since production of

many other important hormones is also decreased

during ageing relative to cortisol (Straub et al.2001).Although the mechanisms underlying immuno-senescence are still being unravelled,it is becoming increasingly clear that many of the physiological changes associated with ageing are characterized by de?cient communication between neuroendocrine and immune systems.Data presented here suggest that ageing is associated with reduced lymphocyte sensitivity to GCs.Glucocorticoid-induced acquired resistance may have an important physiological signi?cance of protecting cells from the dangerous effects of prolonged GC-related immunosuppression.However,the signi?cance of this adaptive pheno-menon is questionable since T -cell proliferation is still profoundly suppressed during ageing (Figure 2).Additionally,altered steroid immunoregulation may have important therapeutic implications in clinical situations where GCs are administered,including treatment of autoimmune diseases,organ transplan-tation and allergies.Clinicians should consider both a patient’s age and psychological status in prescribing steroids as anti-in?ammatory drugs.Chronically stressed elderly subjects may be particularly at risk of stress-related pathology because of further alterations in GC-immune signaling.Elderly individuals who experience chronic stress exhibit poorer immune functions,and thus increased disease vulnerability,than their less stressed counter-parts.Indeed,chronically stressed elderly populations are associated with increased morbidity and mortality rates.Therefore,stress management and psychosocial support should promote a better quality of life

for

Figure 6.The neuroendocrine hypothesis of immunosenescence.During ageing,cumulative neuronal damage produced by stress-related cortisol action in the brain (and )(Sapolsky et al.1986)is associated with decreased central sensitivity to cortisol ()(Raskind et al.1994,Ferrari et al.2001).This speci?c effect is associated with increased cortisol/DHEA ratio ()(Luz et al.2003,Ferrari et al.2004)which in turn may produce more neuronal damage in the brain and further promote thymic involution–due to lack of anti-glucocorticoid effects ().The latter may be related to immunosenescence via two mechanisms:(a)indirectly reducing the output of central na?¨ve T cells and (b)directly acting at the level of peripheral lymphoid cells ()(Luz et al.2002).

Stress and ageing of the immune system 79

the elderly as well as reducing hospitalisation costs for governments.

Acknowledgements

This study was supported by grants from FAPERGS (00/0168.9)and CNPq(551180/01-3).

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《病理生理学》考试知识点总结知识分享

《病理生理学》考试知识点总结 第一章疾病概论 1、健康、亚健康与疾病的概念 健康：健康不仅是没有疾病或病痛，而且是一种躯体上、精神上以及社会上的完全良好状态。 亚健康状态：人体的机能状况下降，无法达到健康的标准，但尚未患病的中间状态，是机体在患病前发出的“信号”. 疾病disease：是机体在一定条件下受病因损害作用后，机体的自稳调节紊乱而导致的异常生命活动过程。 2、死亡与脑死亡的概念及判断标准 死亡：按照传统概念，死亡是一个过程，包括濒死期，临床死亡期和生物学死亡期。一般认为死亡是指机体作为一个整体的功能永久停止。 脑死亡：指脑干或脑干以上中枢神经系统永久性地、不可逆地丧失功能。判断标准：①不可逆性昏迷和对外界刺激完全失去反应；②无自主呼吸；③瞳孔散大、固定；④脑干神经反射消失，如瞳孔对光反射、角膜反射、咳嗽反射、咽反射等；⑤脑电波消失，呈平直线。 ⑥脑血液循环完全停止。 3、第二节的发病学部分 发病学：研究疾病发生的规律和机制的科学。 疾病发生发展的规律：⑴自稳调节紊乱规律；⑵损伤与抗损伤反应的对立统一规律； ⑶因果转化规律；⑷局部与整体的统一规律。 第三章细胞信号转导与疾病 1、细胞信号转导的概念 细胞信号转导是指细胞外因子通过与受体(膜受体或核受体)结合,引发细胞内的一系列生物化学反应以及蛋白间相互作用,直至细胞生理反应所需基因开始表达、各种生物学效应形成的过程。 2、受体上调（增敏）、受体下调（减敏）的概念 由于信号分子量的持续性减少，或长期应用受体拮抗药会发生受体的数量增加或敏感性增强的现象，称为受体上调（up-regulation）；造成细胞对特定信号的反应性增强，称为高敏或超敏。 反之，由于信号分子量的持续性增加，或长期应用受体激动药会发生受体的数量减少或敏感性减弱的现象，称为受体下调（down-regulation）。造成细胞对特定信号的反应性增强，称为减敏或脱敏。 第五章水、电解质及酸碱平衡紊乱 1、三种脱水类型的概念 低渗性脱水是指体液容量减少，以失钠多于失水，血清钠浓度＜130mmol/L,血浆渗透压＜280mmol/L，以细胞外液减少为主的病理变化过程。（低血钠性细胞外液减少）高渗性脱水是指体液容量减少，以失水多于失钠，血清钠浓度＞150mmol/L，和血浆渗透压＞310mmol/L，以细胞内液减少为主的病理变化过程。（高血钠性体液容量减少）等渗性脱水水钠等比例丢失，细胞外液显著减少，细胞内液变化不明显。（正常血钠性体液容量减少）

病理生理学总结重点 (已自动恢复)

病理生理学 水、电解质代谢紊乱 电解质的生理功能和钠平衡： ①维持神经、肌肉、心肌细胞的静息电位，并参与其动作电位的形成。 ②维持体液的渗透平衡和酸碱平衡。 ③参与新陈代谢和生理功能活动。 ④构成组织的成分，如钙、磷、镁是骨骼和牙齿的组成成分。 血浆渗透压升高时：ADH分泌增多，醛固酮分泌减少； 血浆渗透压降低时：醛固酮分泌增多，ADH分泌减少； 循环血量降低时：ADH和醛固酮的分泌都增加。 （一）低渗性脱水 = 低容量性低钠血症 定义与特点：失Na+ 多于失水；血清[Na+ ]<130 mmol/L；血浆渗透压<280 mmol/L 伴 有细胞外液量减少 原因与机制：机体丢Na+、丢水的时候，只补充水而未给电解质。 丢的途径： （1）经肾丢失 利尿剂使用不当（抑制Na＋的重吸收） 醛固酮分泌不足（ Na＋的重吸收不足） 肾实质病变（髓质破坏，不能重吸收Na＋） 肾小管酸中毒（renal tubular acidosis, RTA) （2）肾外丢失 消化道（上消化道：呕吐；下消化道：腹泻） 皮肤（大量出汗，大面积烧伤） 第三间隙积聚（胸水，腹水） 2. 低渗性脱水对机体的影响 （1）细胞内外的水、电解质交换特点：由于细胞外液低渗，水分从细胞外更多地进 入细胞 (2)循环血量的变化：细胞外液丢失为主，循环血量明显减少，易发生休克； (3)整体水平表现：血容量的减少导致细胞间液向血管转移，因此，脱水体征明显； (4)实验室检查：尿钠含量变化（经肾丢失者增高，其余的因为代偿的作用，尿钠降低） 脱(失)水体征：由于血容量减少，组织间液向血管内转移，组织间液减少更明显，病人 出现皮肤弹性减退，眼窝和婴幼儿囟门凹陷。 渴感来自于血浆渗透压的升高，因此本型脱水病人没有明显渴感，并且由于血浆渗透压 的降低，可抑制ADH的分泌。 3.低渗性脱水的治疗：消除病因，适当补液（等渗液为主） （二）高渗性脱水= 低容量性高钠血症 特点：失水多于失钠血清Na+浓度>150 mmol/L 血浆渗透压>310 mmol/L 细胞外液 量明显减少 1. 原因与机制： （1）水摄入减少：水源断绝或摄入困难 （2）水丢失过多： （3）失液未补充： 丢的途径：呼吸道失水（不含任何电解质）皮肤失水（高热，大汗，高代谢率）经肾

病理生理学重点归纳

三种类型脱水的对比 体内固定酸的排泄（肾脏）： 固定酸首先被体液缓冲系统所缓冲，生成H 2CO 3和相应的固定酸盐（根）； H 2CO 3在肾脏解离为CO 2和H 2O ，进入肾小管上皮细胞，即固定酸中的H ＋ 以CO 2和H 2O 的形式进入肾小管 上皮细胞，进一步通过H 2CO 3释放H ＋ 进入肾小管腔； 固定酸的酸根以其相应的固定酸盐的形式 被肾小球滤出； 进入肾小管腔的H ＋ 和固定酸的酸根在肾小管腔内结合成相应的固定酸排出体外。 呼吸性调节和代谢性调节（互为代偿，共同调节）： 呼吸性因素变化后，代谢性因素代偿： 代谢性因素变化后，呼吸性、代谢性 因素均可代偿： 酸碱平衡的调节： 体液的缓冲，使强酸或强碱变为弱酸或弱碱，防止pH 值剧烈变动； 同时使[HCO3-]/[H 2CO 3]出现一定程度的变化。 呼吸的变化，调节血中H 2CO 3的浓度； 肾调节血中HCO3-的浓度。 使[HCO3-]/[H 2CO 3]二者的比值保持20:1，血液pH 保持7.4。 各调节系统的特点： 血液缓冲系统：起效迅速，只能将强酸（碱)→弱酸(碱)，但不能改变酸(碱)性物质的总量； 组织细胞：调节作用强大，但可引起血钾浓度的异常； 呼吸调节：调节作用强大，起效快，30 min 可达高峰；但仅对CO 2起作用； 肾 调节：调节作用强大，但起效慢，于数小时方可发挥作用，3~5 d 达高峰。

酸碱平衡紊乱的类型： 代偿性: pH仍在正常范围之内, 即[HCO3-]/[H2CO3]仍为20:1, 但各自的含量出现异常变化。失代偿性: pH明显异常，超出正常范围。 判定酸碱平衡紊乱的常用指标： pH值：7.35-7.45（动脉血） 动脉血CO2分压（PaCO2）：33-46mmHg，均值40mmHg 标准碳酸氢盐和实际碳酸氢盐(SB/AB)：正常人AB=SB：22-27mmol/L，均值24mmol/L 缓冲碱(BB)：45-52mmol/L，均值48mmol/L 碱剩余(BE)：-/+3.0mmol/L 阴离子间隙(AG)：12-/+2mmol/L，AG＞16mmol/L，判断AD增高代谢性酸中毒

病理生理学重点总结

第二章 疾病概论 1.脑死亡标准 1）呼吸心跳停止 2）不可逆性深昏迷 3）脑干神经反射消失 4）瞳孔散大或固定 5）脑电波消失，成平直线 6）脑血液循环完全停止 第三章 水、电解质代谢紊乱 1、新生儿体液量约为体重的80%，婴儿占75%，学龄儿童占65%，成人占60% 2、细胞外液阳离子 Na+、K+ 阴离子 Cl- 细胞内液阳离子 K+ 、Na+ 阴离子 HPO42- 、蛋白质 3、溶液的渗透压取决于溶质的分子或离子的数目，体液内起渗透作用的溶质主要是电解质。 血浆蛋白质由于其不能自由通透毛细血管壁，对维持血管内外液体的交换和血容量具有十分重要的作用。 4、正常血浆渗透压在280-310mmol/L之间。 5、正常成年人每天至少必须排出500ml尿液才能清除体内的代谢废物。 6、血清Na+浓度的正常范围是130-150mmol/L 7、低钠血症：是指血清Na＋浓度<130mmol/L,伴有或不伴有细胞外液容量的改变。 低容量性低钠血症(hypovolemic hyponatremia)： 特点：失钠多于失水，血清Na+浓度<130mmol/L , 血浆渗透压<280mmol/L，伴有细胞外液量的减少。 又称为低渗性脱水(hypotonic dehydration)。 原因和机制 （1）经肾丢失 1）长期连续使用高效利尿药 2）肾上腺皮质功能不全 3）肾实质性疾病 4）肾小管酸中毒(renal tubular acidosis,,RTA) （2）肾外丢失 1）经消化道失液 2）液体在第三间隙积聚 3）经皮肤丢失 .对机体的影响 （1）细胞外液减少，易发生休克。 （2）血浆渗透压降低，无口渴感，饮水减少；抑 制渗透压感受器，使ADH分泌减少，导致多尿， 低比重尿。 （3）有明显的失水体征。 （4）经肾丢失钠的患者，尿钠含量增多； 肾外因素丢失钠的患者，尿钠含量减少。

病理生理学重点2

能用就用不行就参考参考！嘻嘻 病理生理学 第一章绪论 病理生理学：是一门研究疾病发生、发展、转归的规律和机制的科学。其主要任务是研究疾病发展的一般规律与机制，探讨疾病的本质，为疾病的防治提供理论和实验依据。 第二章疾病概论 名词解释 1.健康：指躯体上，精神上和社会上处于完好的状态。 2.疾病：疾病是指机体在一定条件下由病因与机体相互作用而产生的一个损伤与抗损伤斗争的有规律过程，体内有一系列功能。代谢和形态的改变，临床出现许多不同的病状与体征，机体与外环境间的协调发生障碍。 3.基本病理过程：多种疾病过程中出现的共同的功能、代谢和形态的病理变化。 4.脑死亡：指枕骨大孔以上全脑死亡，为人的实质性死亡。 第三章水、电解质代谢紊乱 知识表格 1.低钠血症

2.高钠血症 3.钾代谢障碍 名词解释 1.低钠血症：指血清Na+浓度<130mmol/L ，伴有或不伴有细胞外液容量的改变。 2.低渗性脱水：即低容量性低钠血症，失Na+多于失水，血清Na+浓度<130mmol/L ，血浆渗透压<280mmol/L ，伴有细胞外液量的减少。 3.水中毒：即高容量性低钠血症，血清Na+浓度<130mmol/L ，血浆渗透压<280mmol/L ，患者有水储留使体液量明显增多，体钠总量正常或增多。 4.高钠血症：血清Na+浓度>150 mmol/L ，血浆皆为高渗状态。 5.高渗性脱水：即低容量性高钠血症，失水多于失钠，血清Na+浓度>150mmol/L ，血浆渗透压>310mmol/L ，细胞外液量和细胞内液的量均减少。 6.盐中毒：即高容量性高钠血症，血容量和血钠均增高。 7.水肿：过多的液体在组织间隙或体腔内积聚称为水肿。 8.脱水热：严重的低容量性高钠血症患者，尤其是体温调节功能发育尚未完全的婴幼儿，易出现体温升高，称为脱水热。主要与散热障碍和体温调节中枢的调定点上移有关。 9.心性水肿：由右心衰竭引起的水肿，特点是水肿先出现在身体的下垂部位。 10.肾性水肿：由肾功能障碍引起的水肿，特点是水肿先出现在组织结构比较疏松的部位如眼睑。 问答题 哪些类型的钠代谢紊乱会导致中枢神经的紊乱，它们的各自的原理又是什么？ 答：低钠血症容易导致脑水肿，患者出现中枢神经系统的症状，如头痛、恶心、呕吐等，严重的可发生脑疝。原理是血钠下降，导致细胞外液渗透压下降，液体移入细胞内，使脑细胞肿胀，引起一些列的中枢神经障碍。 高钠血症容易导致脑细胞脱水，可出现一系列的中枢神经系统的功能障碍的表现，如嗜睡、昏迷等。由于脑细胞脱水，缩小，颅骨与脑皮质之间的血管张力增大，可引起脑出血、蛛网膜下腔出血等。原理是血钠上升，导致细胞外液渗透压上升，液体移出细胞，使脑细胞脱水，引起一些列的中枢神经障碍。

病理生理学重点内容总结

个单选题，分；个简答题，分；一个论述题，分。 疾病概论 ．健康不仅是指没有疾病或病痛，而且是躯体上、精神上和社会上的完好状态休克、缺氧、发热、水肿都是基本病理过程；疾病是机体在一定病因损害下，因自稳调节紊乱而发生的异常生命活动。 ．病因学主要研究的内容是疾病发生的原因及条件，没有病因存在，疾病肯定不会发生；疾病发生的因素有很多种，血友病的致病因素是遗传性因素； . 疾病发生发展机制：包括神经、体液、细胞、分子机制。分子机制中分子病是指由于遗传上的原因而造成的蛋白质分子结构或合成量的异常所引起的疾病。分子病包括：酶缺乏所致的疾病、受体病、细胞蛋白缺陷所致的疾病、细胞膜载体蛋白缺陷引起的疾病； ．疾病发生的条件主要是指那些能够影响疾病发生的各种机体内外因素、它们本身不能引起疾病、可以左右病因对机体的影响促进疾病的发生、年龄和性别也可作为某些疾病的发生条件。疾病发生的条件是指在疾病原因的作用下，对疾病发生和发展有影响的因素，条件包括自然条件和社会条件，某一疾病是条件的因素，可能是另一疾病的原因，条件可促进或延缓疾病的发生； 水电解质紊乱

. 细胞外液中最主要的阳离子是；细胞外液中最主要的阴离子是；细胞内液中最主要的阳离子是细胞内液中最主要的阴离子是 .体液内起渗透作用的溶质主要是电解质，对于维持血管内外液体交换和血容量具有重要作用的物质是蛋白质，肝硬化、营养不良、肾病综合征、恶性肿瘤会引起血浆胶体渗透压下降。 . 低镁血症可以导致低钾血症、低钙血症。低钾血症倾向于诱发代谢性碱中毒。 . 高容量性低钠血症又称为水中毒，特点是患者水潴留使体液明显增多，血钠下降。对于维持血管内外液体交换和血容量具有重要作用的物质是蛋白质。 ..丝虫病引起水肿的主要机制是淋巴回流受阻。 .水肿的发病机制（简答） 血管内外液体交换失平衡。血管内外的液体交换维持着组织液的生成及回流的平衡。影响血管内外液体交换的因素主要有：①毛细血管流体静压和组织间液胶体渗透压，是促使液体滤出毛细血管的力量；②血浆胶体渗透压和组织间液流体静压，是促使液体回流至毛细血管的力量；③淋巴回流的作用。在病理情况下，当上述一个或两个以上因素同时或相继失调，影响了这一动态平衡，使组织液的生成大于回流，就会引起组织间隙内液体增多而发生水肿。 组织液生成增加主要见于下列几种情况：①毛细血管流体静

病理生理学重点

病理生理学 第一章绪论 病理生理学：是一门研究疾病发生、发展、转归的规律和机制的科学。其主要任务是研究疾病发展的一般规律与机制，探讨疾病的本质，为疾病的防治提供理论和实验依据。 第二章疾病概论 名词解释 1.健康：指躯体上，精神上和社会上处于完好的状态。 2.疾病：疾病是指机体在一定条件下由病因与机体相互作用而产生的一个损伤与抗损伤斗争的有规律过程，体内有一系列功能。代谢和形态的改变，临床出现许多不同的病状与体征，机体与外环境间的协调发生障碍。 3.基本病理过程：多种疾病过程中出现的共同的功能、代谢和形态的病理变化。 4.脑死亡：指枕骨大孔以上全脑死亡，为人的实质性死亡。 第三章水、电解质代谢紊乱 知识表格 1.低钠血症

2.高钠血症 3.钾代谢障碍 名词解释 1.低钠血症：指血清Na+浓度<130mmol/L ，伴有或不伴有细胞外液容量的改变。 2.低渗性脱水：即低容量性低钠血症，失Na+多于失水，血清Na+浓度<130mmol/L ，血浆渗透压<280mmol/L ，伴有细胞外液量的减少。 3.水中毒：即高容量性低钠血症，血清Na+浓度<130mmol/L ，血浆渗透压<280mmol/L ，患者有水储留使体液量明显增多，体钠总量正常或增多。 4.高钠血症：血清Na+浓度>150 mmol/L ，血浆皆为高渗状态。 5.高渗性脱水：即低容量性高钠血症，失水多于失钠，血清Na+浓度>150mmol/L ，血浆渗透压>310mmol/L ，细胞外液量和细胞内液的量均减少。 6.盐中毒：即高容量性高钠血症，血容量和血钠均增高。 7.水肿：过多的液体在组织间隙或体腔内积聚称为水肿。 8.脱水热：严重的低容量性高钠血症患者，尤其是体温调节功能发育尚未完全的婴幼儿，易出现体温升高，称为脱水热。主要与散热障碍和体温调节中枢的调定点上移有关。 9.心性水肿：由右心衰竭引起的水肿，特点是水肿先出现在身体的下垂部位。 10.肾性水肿：由肾功能障碍引起的水肿，特点是水肿先出现在组织结构比较疏松的部位如眼睑。 问答题 哪些类型的钠代谢紊乱会导致中枢神经的紊乱，它们的各自的原理又是什么？ 答：低钠血症容易导致脑水肿，患者出现中枢神经系统的症状，如头痛、恶心、呕吐等，严重的可发生脑疝。原理是血钠下降，导致细胞外液渗透压下降，液体移入细胞内，使脑细胞肿胀，引起一些列的中枢神经障碍。 高钠血症容易导致脑细胞脱水，可出现一系列的中枢神经系统的功能障碍的表现，如嗜睡、昏迷等。由于脑细胞脱水，缩小，颅骨与脑皮质之间的血管张力增大，可引起脑出血、蛛网膜下腔出血等。原理是血钠上升，导致细胞外液渗透压上升，液体移出细胞，使脑细胞脱水，引起一些列的中枢神经障碍。

病理生理学重点总结

病理生理学复习重点 考点一： 名词解释 1 病理生理学pathophysiology：是一门研究疾病发生发展规律和机制的科学。 2 疾病disease：是机体在一定的致病原因和条件的作用下，发生的机体自稳态破坏，从而偏离正常的生理状态，引起一系列机能代谢和形态的异常变化，变现为症状体征的社会行为异常，这种异常的生命过程称为疾病。 3 脑死亡：全脑功能不可逆的停止，导致整体功能永久丧失，是现代死亡的概念。其判断标准为大于等于6小时不可逆性昏迷，自主呼吸停止，脑干反射消失，脑电波消失，脑血流停止。 4 疾病的转归prognosis：有康复和死亡两种形式。1、康复rehabilitation：分成完全康复与不完全康复两种。2、死亡death：长期以来，一直吧心跳呼吸的永久性停止作为死亡的标志，包括濒死期、临床死亡期、生物学死亡期。 考点二水电解质紊乱 1 无机电解质主要功能： 1、维持体液的渗透压平衡和酸碱平衡 2、维持神经、肌肉、心肌细胞的静息电位，并参与其 动作电位的形成3、参与新陈代谢和生理功能活动 4、构成组织成分 2 水电解质平衡的调节：在一般情况下，不会因为喝水和吃盐的多少而使细胞外液的渗透压发生显著的改变，当机体内水分不足或摄入较多食盐而使细胞外液的渗透压升高时，则刺激下丘脑的视上核渗透压感受器和侧面的口渴中枢，产生兴奋。也可反射性引起口渴的感觉，机体主动饮水而补

充水的不足，另一反面促使ADH的分泌增多，ADH与远曲小管和集合管上皮细胞管周膜上的V2S受体结合后，激活膜内的腺甘酸环化酶，促使cAMP 升高并进一步激活上皮细胞的蛋白激酶，蛋白激酶的激活使靠近管枪膜含有水通道的小泡镶嵌在管腔膜上，增加了管腔膜上的水通道，及水通道的通透性，从而加强肾远曲小管和集合管对水的重吸收，减少水的排出，同时抑制醛固酮的分泌，间弱肾小管对钠离子的重吸收，增加钠离子的排出，降低了钠离子在细胞外液的浓度，使已经升高的细胞外液渗透压降至正常。反之，当体内水分过多或摄盐不足而使细胞外渗透压降低时，一方面通过抑制ADH的分泌减弱肾远曲小管和集合管对水的重吸收，使水分排出增多，另一方面促进醛固酮的分泌，加强肾小管对钠离子的重吸收，减少钠离子的排出，从而使细胞外液中的钠离子浓度增高，结果已降低的细胞外液渗透压增至正常。 3 心房肽或称心房利钠肽atrialnatriuretic peptide,ANP:是一组由心房肌细胞产生的多肽，约由21-33个氨基酸组成。 4 ANP释放入血后，将主要从四个方面影响水钠代谢：1、减少肾素的分泌2、抑制醛固酮的分泌3、对抗血管紧张素的缩血管效应4、拮抗醛固酮的滞钠离子总用 5 水通道蛋白aquaporins,AQP:是一组构成水通道与水通透有关的细胞膜转运蛋白。 考点三 6 根据血钠的浓度和体液容量来分 1、低钠血症分为低容量性、高容量性、等容量性低钠血症 2、高钠血症分为低容量性、高容量

完整word版,病理生理学重点内容总结,推荐文档

70个单选题，70分；2个简答题，20分；一个论述题，10分。疾病概论 1．健康不仅是指没有疾病或病痛，而且是躯体上、精神上和社会上的完好状态休克、缺氧、发热、水肿都是基本病理过程；疾病是机体在一定病因损害下，因自稳调节紊乱而发生的异常生命活动。 2．病因学主要研究的内容是疾病发生的原因与条件，没有病因存在，疾病肯定不会发生；疾病发生的因素有很多种，血友病的致病因素是遗传性因素； 3. 疾病发生发展机制：包括神经、体液、细胞、分子机制。分子机制中分子病是指由于遗传上的原因而造成的蛋白质分子结构或合成量的异常所引起的疾病。分子病包括：酶缺乏所致的疾病、受体病、细胞蛋白缺陷所致的疾病、细胞膜载体蛋白缺陷引起的疾病； 4．疾病发生的条件主要是指那些能够影响疾病发生的各种机体内外因素、它们本身不能引起疾病、可以左右病因对机体的影响促进疾病的发生、年龄和性别也可作为某些疾病的发生条件。疾病发生的条件是指在疾病原因的作用下，对疾病发生和发展有影响的因素，条件包括自然条件和社会条件，某一疾病是条件的因素，可能是另一疾病的原因，条件可促进或延缓疾病的发生； 水电解质紊乱 1. 细胞外液中最主要的阳离子是Na+ ；细胞外液中最主要的阴离子是Cl-；细 2- 胞内液中最主要的阳离子是K + 细胞内液中最主要的阴离子是HPO 4 2. 体液内起渗透作用的溶质主要是电解质，对于维持血管内外液体交换和血容量具有重要作用的物质是蛋白质，肝硬化、营养不良、肾病综合征、恶性肿瘤会引起血浆胶体渗透压下降。 3. 低镁血症可以导致低钾血症、低钙血症。低钾血症倾向于诱发代谢性碱中毒。 4. 高容量性低钠血症又称为水中毒，特点是患者水潴留使体液明显增多，血钠下降。对于维持血管内外液体交换和血容量具有重要作用的物质是蛋白质。 5..丝虫病引起水肿的主要机制是淋巴回流受阻。 6.水肿的发病机制（简答） 血管内外液体交换失平衡。血管内外的液体交换维持着组织液的生成与回流

病理生理学重点名词解释

病理生理学重点名词解释 1．疾病（disease）是指机体在一定原因作用下，自稳调节机制发生紊乱而出现的异常生命活动过程。 2．病理生理学（pathophysiology）是一门侧重从功能和代谢角度，阐明疾病发生、发展和转归规律的学科。 药物靶标（drug target）是指任何药物进入人体后都是通过作用于特定组织细胞内的特定分子而生效的。这种药物作用的特定分子称为药物靶标。 病理过程（pathologic process）是指不同器官、系统在许多不同疾病中可能出现的共同的、成套的功能代谢的变化。 病因（etiology agents）是指作用于机体引起疾病并赋予该疾病特征性的因素。 先天因素（congenital factors）并不是指遗传物质的改变，而是指那些对发育中的胚胎可能引起损害的因素。其结果是致使胎儿出生时就已患病。该类疾病称为先天性疾病。 疾病发生的条件（predisposing factors）是指在病因作用于机体的前提下，影响疾病发生发展的各种体内外因素。 诱发因素（precipitating factor）是指能够促进和加强某一疾病原因作用的条件因素称为诱发因素，简称诱因。 危险因素（dangerous factor）指某些可促进疾病发生的因素，但尚未阐明是否是该疾病的原因还是条件。 发病学（pathogenesis）主要研究病因如何作用于机体并导致疾病。具体地，它主要涉及疾病发生的基本机制和疾病发生、发展、转归的普遍规律。 完全康复（complete recovery）是指病因去除后，患病机体的损伤和抗损伤反应完全消失、形态结构损伤完全修复、机体功能和代谢完全恢复到正常状态，以及临床症状和体征完全消退。 不完全康复（incomplete recovery）是指原始病因消除后，患病机体的损伤性变化得以控制，但机体内仍存在病理变化，只是机体通过代偿反应维持相对正常的生命活动。 死亡（death）是指机体生命的终结；是指机体作为一个整体（organism as a whole）的机能永久性的停止，而整体的死亡而并不意味着各器官组织同时都发生死亡。

病理生理学期末复习重点

第1章水肿 二、填空题 1、全身性水肿常见类型有⑴心性水肿⑵肝性水肿⑶肾性水肿⑷营养不良性水肿 2、脑水肿可分为⑴血管源性脑水肿⑵细胞中毒性脑水肿⑶间质些脑水肿 3、毛细血管流体静脉压增高的最常见原因是(1) 静脉压增高/充血性心力衰竭，血浆胶体渗透压降低的主 要因素是(2) 血浆白蛋白含量降低。 4、引起肾小球滤过率下降的常见原因是⑴广泛的肾小球病变和⑵肾血量明显减少。 5、肾病性水肿的主要发病机制是(1) 血浆胶体渗透压下降，肾炎性水肿的主要发病机制是(2) 肾小球滤过 率降低。 6、一般的，肝性水肿表现为(1) 肝腹水，心性水肿最早出现部位是(2) 下肢，肾性水肿首先出现于（3） 眼睑有关。 7、全身性水肿的分布特点与⑴重力效应⑵组织结构特点⑶局部血液动力学因素。 8、心性水肿发生的主要机制：(1)心输出量减少 (2)静脉回流障碍。 五、问答题 1、简述血管内外液体交换失平衡的原因和机制。 答：血管内外液体交换失平衡是指组织液的生成大于组织液的回流，使过多的液体在组织间隙或体腔中积聚，发生因素有：①毛细血管流体静压增高，见于心衰、静脉血栓等；②血浆胶体渗透压下降，见于血浆清蛋白减少；③微血管壁通透性增加，见于各种炎症，包括感染、烧伤等；④淋巴回流受阻，见于淋巴管受压或阻塞，如肿瘤、丝虫病等。 2、水肿时引起体内外液体交换失平衡的机制。 答：主要与肾调节功能紊乱有关，机制：①肾小球滤过率下降：广泛的肾小球病变致肾小球滤过面积明显减少和有效循环血量明显减少致肾血流量减少。②肾小管重吸收增加：1）肾血流重分布2）醛固酮增加 3）抗利尿激素增加 4）心房利钠肽分泌减少 5）肾小球滤过分数增加 第2章缺氧 二、填空题 1、低张性缺氧，其动脉血气指标最具特征性的变化是(1) 动脉血氧分压下降。 2、引起氧离曲线右移的因素有⑴酸中毒⑵CO2增多⑶温度升高⑷红细胞内2，3-DPG增加 3、缺氧的类型有⑴循环性缺氧(2)组织性缺氧(3)低张性(乏氧性)缺氧(4)血液性缺氧。 4、发绀是血中(1) 脱氧Hb增加至(2) 5g/dl时,皮肤粘膜呈(3) 青紫色。CO中毒时，皮肤粘膜呈(4) 樱桃 红色。亚硝酸盐中毒时呈(5) 咖啡色色。严重贫血时呈(6) 苍白。 5、低张性缺氧引起的代偿性心血管反应主要表现为⑴心输量增加⑵血液重新分布⑶肺血管收缩⑷毛细血管 增生。 6、CO中毒引起的缺氧是(1)血液性缺氧，其血氧指标变化为⑵血氧含量下降⑶血氧容量下降⑷SaO2正常 (5)PaO2正常(6)动静脉氧含量差下降。 7、缺氧性细胞损伤主要表现为⑴细胞膜⑵线粒体⑶溶酶体的变化。

病理生理学重点总结

《病理生理学》复习重点 一、需要掌握的概念 活性氧、功能性分流、枉失衡说、CO2麻醉、发热激活物、自身输血、P50 二、需要掌握（理解）的知识要点 代谢性碱中毒时发生面部和肢体肌肉抽动的原因 全身体循环静脉压增高的常见原因 阻塞性低容量性低钠血症的临床表现 发热过程中共同的中介环节 血气检测结果为HC03—降低, PaC02升高，提示哪一种酸碱失常 毛细血管前括约肌的缩舒主要由什么调节 最易发生缺血—灌注损伤的器官 休克的可逆性失代偿期表现 对挥发酸进行缓冲的最主要系统 通气不足可见于哪些疾病 三、需要掌握（记忆）的知识要点 酸中毒可影响什么物质对儿茶酚胺的敏感性 休克早期哪些部位血管剧烈收缩，哪些部位改变不明显 左心衰竭引起呼吸困难的病理生理学基础 肝性脑病时，兴奋性递质含量变化特点 蛋白尿的出现反映肾脏的哪些部位有功能和结构的改变 四、需要掌握的重点内容 肺泡通气/血流比例失调的表现形式及其病理生理学意义 酸中毒对心血管系统的影响 严重肝脏疾病病人在并发碱中毒时易出现肝性脑病的机理 低容量性低钠血症病人容易发生休克的原因 肝功能衰竭病人血钾的变化及机理 肾在调节酸硷平衡中的作用

急性肾功能衰竭(Acute renal failure)∶在各种致病因素下，引起肾泌尿功能急剧下降，导致排泄功能及调节功能障碍，以致代谢产物潴留,水、电、酸碱平衡紊乱。 一、原因与分类 1、肾前性急性肾衰(功能性肾衰) prerenal failure or functional renal failure 原因：低血容量(大出血、创伤、脱水等) 心输出量降低(心衰) →肾血液灌流量急剧ˉ 血管床容积扩大(过敏性休克) 2、肾性急性肾衰(器质性肾衰) Intrarenal failure or parenchymal renal failure 原因：肾实质病变 (1)急性肾小管坏死:约占2/3 ▲肾缺血 ▲肾中毒：重金属，药物和毒物； 生物毒素(蛇毒)； 内源性肾毒物(Hb、肌红蛋白) (2)肾脏本身疾病 肾小球性疾病:(肾小球肾炎、狼疮性肾炎) 间质性肾炎 血管性疾病:恶性高血压，双侧肾动脉血栓形成或栓塞等。 3、肾后性急性肾衰（阻塞性肾衰）postrenal failure or obstructive renal failure 原因：双侧尿路结石 盆腔肿瘤→尿路梗阻 前列腺肥大 药物结晶等 二、发病机制 1.肾血流量ˉ (1)肾灌注压ˉ (2)肾血管收缩：交感-肾上腺髓质系统兴奋；RAA激活；前列腺素产生ˉ (3)肾缺血-再灌注损伤→肾血管内皮细胞受损、肾小管坏死 2.肾小管损害 3.肾小球超滤系数ˉ（反映肾小球的通透能力，取决于滤过面积和滤过膜通透性。） 三、少尿型急性肾衰分期及机能代谢变化 1.少尿期 (1)尿的变化：▼尿量:少尿(<400ml/天)或无尿(<100ml/天) ▼尿成分：肾小管损害有关 (2)水中毒 少尿 分解代谢加强，内生水↑→水潴留→稀释性低钠血症→细胞水肿 输液过多 (3)代谢性酸中毒 酸性产物排出↓ 肾小管泌H+、NH4+↓，HCO3–重吸收↓→[NaHCO3]/ [ H2CO3] ＜ 20/1→代谢性酸中毒

病理生理学考试重点知识总结

病理生理学 第一章绪论 1.病理生理学：研究疾病发生、发展过程中功能和代谢改变的规律及其机制的学科。其主要任务是揭示疾病的本质。 2.发展简史：实验病理学 3.未来趋势：转化医学、个体化医疗 第二章疾病概况 1.健康：健康不仅是没有疾病或衰弱现象，而是躯体上、精神上和社会适应上的一种完好状态。 2.疾病：在一定病因作用下，机体内稳态调节紊乱而导致的异常生命活动过程。 3.疾病发生的原因——病因（致病因素） 直接引起疾病发生的特定因素（不可少性） 赋予疾病以特征（特异性） 4.病因的分类 生物性因素 理化性因素 营养性因素 遗传性因素 先天性因素 免疫性因素 心理和社会因素 5.疾病发生的条件 能够促进或缓解疾病发生的某种机体状态或自然环境。 本身没有致病性（不绝对）；可影响病因对机体的作用。 6.疾病发生发展的一般规律 1）损伤与抗损伤 疾病中，损伤与抗损伤的斗争贯穿始终，是推动疾病发生的基本动力。 两者的力量对比决定疾病的发展方向和转归。 2）因果交替 3）局部和整体 7.疾病发生的基本机制 1）神经机制 乙型脑炎病毒破坏CNS 乙型脑炎 有机磷农药抑乙酰胆碱酯酶ACh堆积 2）体液机制 体液性因子——维持内环境稳定的重要因素 主要种类全身性作用（组胺、儿茶酚胺等） 局部性作用（内皮素、神经肽、细胞因子等）

内分泌（激素） 作用方式旁分泌（神经递质、血管活性物质） 自分泌（生长因子） 3）细胞机制 直接损伤 细胞膜功能障碍 细胞器功能障碍 间接作用 4）分子机制 分子生物学、分子病理学、分子医学 分子病－遗传物质或基因变异 基因病－基因突变、缺失或表达调控障碍 单基因病 多基因病（多因子疾病）8.疾病的转归 康复完全 不完全 死亡 第三章水、电解质代谢障碍 第一节水、钠代谢紊乱 钠水出入平衡 水平衡：

病理生理学考试重点整理

名解、填空、考点、 疾病：疾病是机体在一定病因作用下，机体内稳态调节紊乱而导致的异常生命活动过程。健康：不仅是没有疾病或衰弱现象，而且是躯体上，精神上和社会适应上的一种完好状态。亚健康：介于疾病与健康之间的生理功能低下的状态。此时机体处于非病、非健康并有可能趋向疾病的状态。表现为“三多三少”：主诉症状多、自我感觉不适多、疲劳多；活力低、反应能力低、适应能力低，但机体无器质性病变证据。 分为躯体性亚健康状态，心理性亚健康状态，人际交往性亚健康状态。 疾病发生的原因（病因）：指能引起某一疾病的特定因素，是引起疾病必不可少的，赋予疾病特征或决定疾病特异性的因素。又称致病因素。包括：生物因素、理化因素、营养因素、遗传因素、先天因素、免疫因素、心理和社会因素。 遗传易感性：指由某些遗传因素所决定的个体患病风险，即相同环境下不同个体患病的风险。如糖尿病患者是否发生肾病因人而异。（由遗传因素决定的个体易于罹患某种疾病的倾向性。） 条件:在病因作用于机体的前提下，能促进或减缓疾病发生的某种机体状态或自然环境。 诱因：其中能加强病因的作用而促进疾病发生发展的因素。 恶性循环：在一些疾病或病理过程因果交替的链式发展中，某几种变化互为因果，形成环式运动，而每一次循环都使病情进一步恶化，称为疾病发生发展中的恶性循环。 脑死亡：是指全脑功能（包括大脑，间脑和脑干）不可逆性的永久性丧失以及机体作为一个整体功能的永久性停止。 判定标准： 1、自主呼吸停止，人工呼吸15分钟仍无自主呼吸； 2、不可逆性深昏迷； 3、颅神经反射（瞳孔反射、角膜反射、吞咽反射、咳嗽反射）均消失； 4、瞳孔散大或固定； 5、脑电波消失； 6、脑血流循环完全停止。 意义：有助于判定死亡时间；确定终止复苏抢救的界限，减少人力及经济消耗；为器官移植创造良好的时机和合法的依据。 低渗性脱水（低容量性低钠血症）【概念】：低渗性脱水特点是①失Na+多于失水；②血清Na+浓度＜130mmol/L；③血浆渗透压＜280mmol/L；④伴有细胞外液的减少。 问答 低渗性脱水（低容量性低钠血症）最容易发生休克的原因？ 1、通过肾丢失以及肾外丢失的三条途径导致细胞外液丢失 2、细胞外液丢失导致细胞内为高渗透状态，水向细胞内转移进一步转移，细胞外液减少。 3、血浆渗透压降低，无口渴感，故机体虽然缺水，但不能很快的通过喝水补充体液。 4、早期细胞外液渗透压降低，抗利尿极速分泌少，早期多尿，更加重了集体的缺水。 低容量性高钠血症（高渗性脱水）【概念】：特点： （1）失水多于失钠 （2）血清钠离子浓度>150mmol/L （3）血浆渗透压>310mmol/L

病理生理学知识点总结

脑死亡的概念及其诊断标准 全脑功能(包括大脑、间脑和脑干) 不可逆的永久性丧失以及机体作为一个整体的功 能永久性停止。 1.不可逆性昏迷和大脑无反应性 2.脑神经反射消失 3.无自主呼吸 4.脑电波及诱发电位消失 5.脑血液循环完全停止 低渗性脱水对机体的影响 1、易发生休克：细胞外液减少，水份向细胞内转移。 2、脱水体征明显：血容量减少→血液浓缩→血浆胶体渗透压升高→组织液进入血管，组织间液明显减少，皮肤弹性丧失、眼窝囟门凹陷。 3、尿量变化：早期不明显（渗透压↓→ADH↓），晚期少尿（血容量↓→ADH↑）。 4、尿钠变化：经肾失钠者尿钠增多；肾外因素所致者尿钠减少（血容量、血钠↓→醛固酮↑）。 高渗性脱水对机体的影响 1、口渴感：刺激渴觉中枢，产生渴感，主动饮水。 2、尿少：细胞外液渗透压升高，引起ADH增多，尿量减少，比重增高。 3、细胞内液向细胞外转移：细胞外高渗，细胞内液向细胞外移动，细胞内液也减少。 4、中枢神经功能紊乱：细胞外液高渗使脑细胞脱水，和出现局部脑内出血和蛛网膜下出血。 5、尿钠变化：早期（血管容量减少不明显，醛固酮分泌不增多）变化不明显或增高。晚期（血容量减少，醛固酮分泌增多）减少 6、脱水热：由于皮肤蒸发减少，散热受到影响，导致体温升高。 水肿的机制 1、毛细血管内外液体交换失平衡导致组织液的生成多于回流，从而使液体在组织间隙内 积聚。此时细胞外液总量并不一定增多。 ①毛细血管流体静压增高→有效流体静压增高→平均实际滤过压增大→组织液生成增 多，超过淋巴回流的代偿能力→引起水肿 ②血浆胶体渗透压降低→有效胶体渗透压降低→平均实际滤过压增大→组织液生成增 多 ③微血管壁通透性增加→血浆蛋白滤出→毛细血管内胶体渗透压降低，组织胶体渗透 压增高→有效胶体渗透压降低→溶质及水分溶出 ④淋巴回流受阻，代偿性抗水肿作用减弱，水肿液在组织间隙中积聚。 2、体内外液体交换失平衡全身水分进出平衡失调导致细胞外液总量增多，以致液体在组织间隙或体腔中积聚。 ①肾小球滤过率下降 ②肾小管重吸收钠水增多（肾血流重分布、心房钠尿肽分泌减少、醛固酮分泌增多 抗利尿激素分泌增加）

病理生理学期末考试重点

单选： 1.上消化道出血（肝功能不全者）引起肝性脑病的原因？（血液中蛋白质经肠细菌分解产生氨 2.血钾、钠的范围（Na:130--150mmol/L K: 3.5--505mmol/L) 3.假性神经学说中的两种物质（苯乙醇胺，羟苯乙醇胺） 4.低钾血症心电图（ST段下移，病理性U波） 5.高钾血症的心电图变化 6.水肿率先发生的部位（心性，肾性等） 7.胶体渗透压的方向，构成 8.何种物质使血红蛋白Fe2+变成Fe3+（亚硝酸盐） 9.什么情况下排酸性尿（代酸，低钾血症伴碱中毒——反常性酸性尿） 10.失血性休克-----肾衰尿少机制（肾血管收缩，滤过减少，代谢产物积聚） 填空： 休克分期：缺血，淤血，衰竭 DIC分期：高凝期，消耗性低凝期，继发性纤溶亢进期 肝性脑病学说：氨中毒学说，假性神经递质学说，氨基酸失衡学说，GABA学说 缺氧分类：低张性缺氧，血液性缺氧，循环性缺氧，组织性缺氧 简答 1.休克分期及微循环特点 （1）微循环缺血期特点：少灌少流，灌少于流，组织呈缺血缺氧状态； （2）微循环淤血期特点：灌而少流，灌大于流，组织呈淤血性缺氧状态 （3）微循环衰竭期特点：不灌不流，血液局凝，组织细胞无血供。甚至出现毛细血管无复流现象，即在输血补液治疗后，血压虽可一度回升，但微循环灌流仍无明显改善，毛细血管中淤滞停止的血流也不能恢复流动的现象。 2.DIC分期，病因症状 P191 发生机制：（1）组织因子释放，外源性凝血系统激活，启动凝血过程； （2）血管内皮细胞损伤，凝血、抗凝血失调； （3）血细胞大量破坏，血小板被激活； （4）促凝物质进入血液。 3.各类型缺氧相关参数指标 缺氧：组织供养减少或不能充分利用氧，导致组织代谢、功能和形态结构异常变化的病理过程称为缺氧。 血氧分压：为物理溶解于血液中的氧所产生的张力，又称血氧张力。 血氧容量：是指氧分压为150mmHg，温度为38℃时，100ml血液中的血红蛋白（Hb）所能结合的氧量，即Hb充分氧合后的最大携氧量，取决于血液中的Hb的含量及其与O2结合的能力。 血氧含量：为100ml血液中实际含有的氧量，包括物理溶解和化学结合的氧量，因正常时物理溶解的氧量仅为0.3ml/dl，可忽略不计。血氧含量主要取决于Hb的含量和结合O2。 血红蛋白氧饱和度，简称血氧饱和度，是指血液中氧合Hb占总Hb的百分数，约等于血氧含量与血氧容量的比值。 低张性缺氧（乏氧性缺氧）：以动脉血氧分压降低、血氧含量减少为基本特征的缺氧。原因：1.吸入气氧分压低 2.外呼吸功能障碍 3.静脉血分流入动脉

病理生理学重点

是指现的共同的、成套的功能代谢和形态结构的病 是指作用于机体 是指在病因作用 疾病发生发展的各种体 是指疾病的用与机体后，机体产生一定的变化，这些变化在一定的条件下又引起另一些变化，即原始致病因素引起的后果，可以在一定条件下转化为另一些变化的原因，如此原因结果不断交替，相互转化，推动疾病的 化都是机体损害加重，病情进行性恶化，最终 hyponatremia ） 当肾排水能力降低而又摄入过多的水时，因大量的水分在体内储留所造成的细胞内外液过多并呈低hypernatremia, hypertonic dehydration ) 又称高 渗性脱水，其特征是失水多于失钠，血清钠浓度>150ml/L,血浆渗透hyponatremia, hypotonic dehydration) 又称低渗性脱水，其特征是失钠多于失水，细胞外液渗透压低于280mmol/L ，血清钠浓度低于 isotonic ）是指机体的水和钠以等渗比例丢失，或失液后经机体调节血浆渗透压仍在正常范围，血清钠 浓度为135~145mmol/L （或mEq/L ），血浆渗透压。 L （或mEq /L ）。 高钾血症(hyperkalemia) 是指L 。 细胞外液胞内液K/细胞外液k 的比值增大，静息状态下细胞内液k 外流增加，使静息电位负值增大，与阈电位之间的距离增大，细胞兴奋性降低 去极化阻滞细胞外液K 浓度急剧升高，细胞内液 K/细胞外液k 的比值更小，使Em 值下降或几乎接近于Et 水平，Em 值过小，肌肉细胞膜上的快钠通道失活，细胞是指由生 成过多，或肾脏排酸减少，以及HCO3-大量丢失，导致血浆HCO3-浓度原指 因CO2吸入过多，导致血浆H2CO3 种以上酸碱平衡紊乱同CO2 潴留使者出现头痛，头晕，烦躁不安，言语不清，扑翼样震颤，精神错乱， 为物理溶解于血下，即在38℃和血红蛋白完全氧合的条件下，用PCO2为的气体平衡 后所测得的血浆HCO3-在实际氧饱和度和PaCO2条件下所测得血浆HCO3浓度，正常值应 包括HCO 3-、Hb -和Pr -等。 正常值：45～55 指标血浆滴定pH 至时所需无氧酵解途径生成乳酸，乳酸过多超出肝脏 的利用能力或严重肝脏疾患造成乳酸利用障碍导致血液中乳酸浓度严重升高，引起代谢性酸加速，大量脂肪酸进入肝脏而形成过多酮体，通体酸性较强，当其量超过外周组织的氧化能力及肾脏的排除能力时，血中酮体变会蓄积， 浆中物理溶解的氧和与Hb 化学结合的氧。当PO2为（100mmHg ）时，100ml 血浆中呈物理溶解状态的氧约为，化学 19ml 。 指当毛细Hb 平均浓度增加至50g/L(5g/dl)以上（SaO2≤80%～85%） 温调定点并 未发生移动，而是由于体温调节障碍和散热障碍及产热器官功能异常，体温调节不能将体温控制在与调定点相适应的水平， 高温诱导下所生成的一 指如机体，则可表现为一个动态的连续过程，最终导致内环境紊乱，引起 是细胞的结构蛋白（称为结构性HSP ），其主要功能是帮助蛋白质进行正确的折叠、移位、维持以及降解，因此被称? 应激 织损伤等原因可是血浆中某些蛋白质浓度迅速身高，这种反应称为急性期反应，这种蛋白质 的，以组织有效循环血液流量急 剧降低为特征，并导致细胞功能、结构损伤和各重要器官机能代谢紊乱的复杂的 胰腺血液灌流持续减少，缺血，缺氧和酸中毒，使胰腺外分泌细胞受损，溶酶体肿胀，破裂并释放出组织蛋白酶等，后者分解胰腺组织蛋白产生低分子量的多 发或导致的急性肾功能衰竭，这种衰竭早期为功能性的，晚期则发展为气质新的，其共同临 床表现时少尿，氮质血症，高钾血症和代谢性休克发展功能衰竭时，给临床治疗带来巨大的困难，通常称此期为不可逆休克即高排点为心输出量增加，动脉血压下降，中心静脉压正常或升高而总外周力低，心输出量也降低血液循环（门静脉循环和体循环）抵达远隔器官的过程称细菌移位。 功能降低和对感染易感性增加的过于强烈的内 在严重粘膜屏蔽功能受损或衰竭时，肠内致病菌和内毒素可经肠道移位而导致肠源性感染。 则会导致炎症反应和免疫功能更为严重的紊乱，对机体产生更强的在外周血涂片中可见一些带刺的收缩红细胞，可见新月形、盔甲形等形态各异的红细胞碎片，由于裂体细胞脆性高，很容易发生溶血，所以称为微血管病性溶血涂片中出现一些特殊的形态各异的红细胞其段的存在，原理如果受检血浆中存在FDP/FgDP 的X 片段和纤维蛋白单