PATHOPHYSIOLOGY OF

COPD
• Chronic obstructive pulmonary disease is defined common preventable
and treatable disease characterized by persistent respiratory symptoms
and airflow limitation that is due to airway or alveolar abnormalities
usually caused by significant exposure to noxious particle or gases and
influenced by host factor including abnormal lung development .

• According to criteria set by the GOLD airflow obstruction is present when

there is a reduction of the postbronchodilator FEV1 /FVC ratio below 0.7
and its severity is graded by the percentage of the postbronchodilator FEV1
of the predicted normal FEV1.
Classification of Airflow Limitation in Patients
with FEV1 /FVC < 0.7
A persistent reduction in FEV1 /FVC is the defining physiological feature of
COPD.

Typical physiological features

• Increased airway resistance, increased residual volume (RV)
• Increased RV/total lung capacity ratio (RV/TLC)
• Decreased inspiratory capacity
• A decreased maximum voluntary ventilation (MVV)
• Abnormal distribution of ventilation,
• Ventilation–perfusion mismatching
AIRFLOW OBSTRUCTION
• The low FEV1 and low FEV1 /FVC in COPD are not reversible with inhaled
bronchodilators,
• Thus, COPD differs from asthma, in which inhaled bronchodilators can
produce large improvements in FEV1 .
• A reduced FEV1 with a normal FEV1 /FVC and normal TLC -nonspecific and
infrequently progresses to COPD.
• The FEV1 is the result of the balance between the elastic recoil of the lungs
promoting expiratory flow and the resistance of the airways that limits flow
during performance of an FVC.
• In lungs affected by COPD, maximal expiratory flow diminishes as the lungs
empty because the lung parenchyma provides progressively less elastic recoil
and the cross-sectional area of the airways falls leading to an increase in
airway resistance.
• The decrease in flow coincident with the decrease in lung volume.
• In mild COPD the abnormality in airflow is evident only at lung volumes at or
below functional residual capacity.
• In advanced COPD, the entire decreased expiratory flow.
• Decreased elastic recoil (“emphysema”) from increased airway resistance
(“small airway disease”) as the cause for the reduced FEV1 .
Analysis of reduced maximum expiratory flow in COPD from maximum expiratory flow versus lung recoil pressure curves. With
loss of lung recoil pressure – that is, “emphysema” (heavy interrupted line) – the slope of the flow–pressure curve remains
normal, but the curve terminates at lower pressure than normal.
With intrinsic airway obstruction – that is, “bronchitis” – the slope is reduced.
Increased airway collapsibility, which may be a result of decreased elastic recoil, causes the curve to be displaced to the right.
• There is wide variability in COPD in the relationships between FEV1 ,
exercise tolerance, and quality of life.
• PaO2 and oxygen saturation usually remain near normal until the FEV1 has
decreased to about half of the predicted normal
• Thus, other causes of hypoxemia or an elevated PaCO2 , such as the
obesity hypoventilation syndrome, should be considered in patients with
abnormal arterial blood gases and only mild to moderate COPD.
• Similarly, pulmonary hypertension and right ventricular failure do not
occur unless COPD is severe and associated with chronic hypoxemia .
ABNORMAL DISTRIBUTION OF VENTILATION
AND VENTILATION–PERFUSION MISMATCHING
• Ventilation–perfusion mismatching that is characteristic of COPD.
• Abnormality in the distribution of ventilation is evident in the pattern of nitrogen
washout during breathing of 100% oxygen.
• The nitrogen washout is delayed because of regions that are poorly ventilated,
• Shape of the nitrogen washout curve reflects compartments with different
washout rates due to regional differences in compliance and airway resistance.
• Radioisotopic ventilation scanning with xenon also reveals regional heterogeneity
of ventilation in COPD.
• The multiple inert gas elimination technique (MIGET) demonstrated different
ventilation–perfusion patterns among patients with advanced COPD .
• In one pattern, the so-called type A COPD, there is a substantial amount of
ventilation distributed to high ventilation–perfusion regions.
• In a second pattern, called type B COPD, there is a substantial amount of
pulmonary blood flow perfusing low ventilation regions.
• Ventilation–perfusion mismatching accounts for essentially all of the
reduction in PaO2 that occurs in COPD, so modest elevations of the inspired
oxygen concentration are effective in treating hypoxemia.
Ventilation–perfusion distributions in three persons with COPD determined by the multiple inert gas
elimination technique (MIGET). A. Regions of high ventilation–perfusion characteristic of “emphysematous,”
type A COPD. B. Regions of low ventilation–perfusion characteristic of “chronic bronchitis,” type B COPD. C.
Regions of both high and low ventilation–perfusion characteristic of many people with COPD. In the normal
person, not shown, ventilation–perfusion virtually overlaps and peaks at about a ventilation–perfusion ratio of
HYPERINFLATION
• Increases in TLC, FRC,RV, and RV/TLC common in COPD.
• They displace the diaphragm into a flattened position causing a number of
adverse effects .
• Put the thoracic cage at a mechanical disadvantage so that inspiration
requires work rather than being passively assisted by the elastic recoil of the
chest wall.
• Increase further with exertion because reductions in airflow in diseased lungs
reduce expiratory volume during rapid breathing.
• This phenomenon, called dynamic hyperinflation, adds to the workload on
the inspiratory muscles
• Dynamic hyperinflation is an important mechanism of dyspnea with exertion
in COPD.
Detrimental effects of hyperinflation on diaphragmatic function.

Hyperinflation causes flattening of the diaphragm, which

(1) decreases the zone of apposition between the diaphragm and
the abdominal wall, hindering rib cage movement;
(2) shortens diaphragmatic muscle fiber length, decreasing the
force that can be generated by the diaphragm;
(3) increases the radius of curvature of the diaphragm, thereby
decreasing transpulmonary pressure (at constant tension); and
(4) directs diaphragmatic muscle fibers medially, impairing inflation
with diaphragmatic contraction.
DYSPNEA
• People with COPD typically seek medical care because shortness of breath
limits their activities and quality of life.
• Dyspnea is seldom a complaint until the FEV1 has fallen below about 60%
of predicted.
• Correlation between FEV1 and exercise limitation is not strong.
• Some individuals are relatively free of dyspnea despite a severely reduced
FEV1 .
• Commonly, the discomfort associated with breathing is associated with
inspiration rather than expiration.
• An increased effort relating to the pressures needed from the respiratory
muscles an important factor in causing the dyspnea associated with COPD.
• Signals of “length-tension inappropriateness” from the respiratory muscles
due to hyperinflation are another factor.
• Dynamic hyperinflation, exaggerates these problems for respiratory
muscles.
• Impulses from airways undergoing abnormal dynamic compression during
exhalation.
• Hypoxemia and hypercapnia play only a small role during periods of clinical
stability.
• Oxygen administration may decrease breathlessness by reducing ventilation
during exertion.
PHYSIOLOGICAL–PATHOLOGICAL
CORRELATIONS
• Airways 2 mm or less are the principal sites of increased airway resistance
in COPD.
• Small airway resistance in COPD was considered to be a combined result
of emphysema and multiple anatomic abnormalities narrowing the small
airways.
• Emphysema and small airway pathology are both common in individuals
with COPD.
• Fixed reduction in airflow is associated with several specific pathologic
findings in the small airways of advanced COPD.
• Small airways in COPD typically show goblet cell metaplasia, replacement of
Clara cells with mucus-secreting cells, and infiltration of the airway walls by
inflammatory cells.
• Increased connective tissue in the subepithelial and adventitial
compartments of the airway walls.
• Alveolar tissue surrounding small airways normally provides radial traction
on bronchioles.
• Loss of these bronchiolar attachments as a result of proteolytic destruction
results in airway distortion, narrowing, and instability
Pathologic lesions in small airways in COPD. Multiple
abnormalities lead to partial obstruction of the lumen and
altered shape and mechanical properties of the airways.
There is a significant loss of visible airways before radiographic emphysema is
present.
Loss of small airways reaching 90% in severe COPD.
Pathologic loss of terminal airways in advanced disease will contribute
significantly to the small airway resistance ,severe wall thickening or mucus
plugging that obscures the lumen.
More severe airflow obstruction is associated with increases in thickness of
all components of the airway wall.
• The greatest relative increase in components of the airway wall is in the
connective tissue–rich adventitial layer
• Epithelial layer, the lamina propria, and the smooth muscle–containing
layer increases in advanced disease
• Small airway mucus plugs associated with airflow limitation in severe
disease.
• Thus, emphysema occurs late in the development of COPD and appears
to have a limited role in causing the airflow obstruction in early COPD.
PATHOGENETIC MECHANISMS

• COPD represents the clinical expression of complex alterations in structure

and function of alveolar tissue and small airways.
• Inflammation, cell proliferation, apoptosis, altered phenotype of lung cells,
and remodeling of the extracellular matrix .
• Mediators, most notably proteinases, oxidants, and cytokines, are involved
in these processes.
The pathogenesis of COPD from smoking

.
 INFLAMMATION
Innate Immune Responses
Inflammation occupies a central role in the pathogenesis of COPD.
Smoking and other types of inhaled irritants lead to recruitment of innate
inflammatory cells to the lungs and airways
Products of these recruited cells injure lung tissue and disrupt normal
mechanisms of lung repair.
Other indicators of inflammation are increased inflammatory cells in
bronchoalveolar lavage fluid (BALF) and sputum.
Elevations in WBC, neutrophil, or liver-derived acute phase reactants.
Inflammatory cells include predominantly neutrophils, macrophages, and
sometimes eosinophils, but also dendritic cells and lymphocytes.
BALF contains many fold increases in macrophages.
Alveolar macrophages release proteinases ,degrade the extracellular
matrix of the lung, make chemotactic factors that recruit other
inflammatory cells.
Structural cells of the lungs in COPD produce proteinases and chemotactic
factors for inflammatory cells.
Expression of IL-8, MIP-1α, and monocyte chemoattractant protein-1
(MCP-1), for example, are upregulated in bronchiolar epithelium in COPD.
Peptides of elastin are chemotactic for inflammatory cells and may act as
epitopes for T-cell responses.
Overexpression of cytokines, such as IL-13 or γ-interferon by lung cells
leads to emphysema via innate immune response..
Acquired Immune Responses
• Cellular and humoral immunity may also be involved in emphysema
pathogenesis.
• CD4+ and CD8+ T cells and B cells accumulate in alveolar and airway tissue in
COPD and form BALT in the walls of small airways.
• The increasing BALT presence in small airways correlates with severity of
GOLD stage.
• Exposure to antibodies directed at endothelial cells alone elicits alveolar
septal cell destruction and emphysema.
• Antigens for immunologically driven emphysema in patients include
microbial pathogens, peptides altered by tobacco smoke, and peptides
released from lung extracellular matrix.

• Accelerated emphysema in smokers with HIV, but that may be complicated

by direct virus infection inducing macrophage alterations, rather than
suppression of acquired immune responses.
PROTEINASE–ANTIPROTEINASE
IMBALANCE
• α1 -AT deficiency associated early-onset emphysema.
• Proteinase excess as an important mechanism in emphysema development.
• Serine proteinases; neutrophil elastase, and several matrix
metalloproteinases.
• It is notable that neutrophils, which are the source of neutrophil elastase
and MMP-12 from alveolar macrophages are related to continued smoking.
• Although neutrophil elastase and its main inhibitor α1 -AT have
predominated the proteinase–antiproteinase imbalance hypothesis,
• Destruction of lung elastin and other matrix components,process
cytokines and surface receptors involved in the inflammatory and
immune responses.
• Inflammatory cells may not be the exclusive sources of the proteinases as
structural cells also produce matrix-degrading proteinases.
OXIDANT–ANTIOXIDANT IMBALANCE
• Reactive oxygen species in cigarette smoke or released by inflammatory
cells and structural cells lead to lung injury.
• Up to 20 mg of tar may be deposited in a smoker’s lung per cigarette
smoked.
• The gas phase of tobacco smoke contains 10-15 organic radicals per puff of
smoke, short-lived and reactive than the radicals in the particulate phase.
• In addition, tobacco smoke appears to “prime” neutrophils and alveolar
macrophages to generate elevated amounts of reactive oxygen species,
such as hydrogen peroxide, hydroxyl radicals, and superoxide radicals.
• The lung tissue of smokers contains significantly more iron than that of
nonsmokers, providing a catalyst for the production of hydroxyl radicals
from H2O2 .
• Increased production of neutrophil myeloperoxidase, yielding oxidized
halogens such as hypochlorous acid (HOCl).
• Oxidants inactivate proteins, such as protease inhibitors (α1 -AT and
secretory leukoprotease inhibitor), and histone deacetylase 2 (HDAC2),
involved in anti-inflammatory responses.
• Oxidants can affect lipids, DNA, and some specific end products, such as 4-
hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2′-deoxyguanosine (8-OHdG),
may be markers of COPD.
• Oxidants facilitate proteinase-mediated extracellular matrix degradation by
enhancing matrix molecule susceptibility to proteolytic cleavage.
APOPTOSIS AND SENESCENCE

• Emphysematous human lung specimens demonstrate increased apoptotic

and senescent cells compared to healthy lung specimens.
• An early theory of emphysema development was that alveolar vascular
destruction preceded loss of alveolar tissue.
• Blockade of vascular endothelial growth factor (VEGF) signaling in alveolar
endothelial cells or genetic downregulation of VEGF production in alveolar
epithelium produces apoptosis and noninflammatory emphysema.
• Cigarette smoke induces apoptosis of several lung cell types.
• BICD1 gene polymorphism linked to emphysema encodes for a protein in
the apoptosis pathway.
• Accelerated aging results in emphysematous changes.
• Lung fibroblasts isolated from human lungs with COPD demonstrate
increased markers of senescence and senescent fibroblasts do not maintain
the extracellular matrix.
• Telomeres in human COPD relates to inflammatory cell telomere
shortening, with telomere length being a biomarker of chronic lifelong
inflammatory excess present in individuals with COPD.
MUCUS HYPERSECRETION

• Airway mucus is a normal protective barrier that is constantly replenished

• Mucin glycoproteins, main components of mucus, have a core protein rich
in serine and threonine.
• Mucus is secreted from submucosal glands and airway goblet cells.
• In COPD there is hyperplasia of goblet cells and hypertrophy of glands with
an increase in the ratio of glandular mucus cells to serous cells.
• COPD associated with an alteration of the mucus proteins (MUCs) to favor a
predominance of MUC5B over the typical MUC5AC form, and an increase in
the MUC2 form.
• Other alterations in the mucus layer in COPD include greater acidity, less
mucin glycosylation, and decreased antimicrobial peptides.
• Mediators responsible for mucus hypersecretion include proteinases,
cytokines, oxidants, and epidermal growth factor receptor (EGFR) ligands.
• Symptoms of mucus hypersecretion are common complaints in individuals
with COPD.
• Extent of small airway luminal obstruction by mucus correlated with the
GOLD stage and was inversely correlated with survival after lung volume
reduction surgery.
• Whether the mucus glycoproteins are a beneficial factor that mark the
degree of inflammation (e.g., a biomarker of inflammation) or are
themselves a pathologic factor in the severity of symptoms or progression
of disease is an important question.
PATHOGENESIS OF EMPHYSEMA
GENERAL CONCEPTS
• Emphysema is defined as “a condition of the lung characterized by
abnormal, permanent enlargement of airspaces distal to the terminal
bronchiole, accompanied by destruction of their walls, and without obvious
fibrosis.”
• Increased collagen per unit volume of airspace wall in emphysematous
tissue and active expression of elastin production..
• Degradation of lung elastin by elastase activity from inflammatory cells is
probably the predominant mechanism for emphysema in most smokers.
• Biology of emphysema includes inflammatory cell recruitment, proteinase–
antiproteinase imbalance, oxidant–antioxidant imbalance, and responses of
lung cells to proteinases and oxidants from inflammatory cells and to
constituents of tobacco smoke.
• It may also involve humoral and cellular immunity.
• Degradation of extracellular matrix components besides elastin, particularly
collagens, may be an important feature.
• In some situations, apoptosis of lung cells may precede degradation
of extracellular matrix.
• Senescence of lung cells, a recently identified phenomenon in
emphysema, but suggests that lung repair mechanisms are
depressed.
• According to the proteinase–antiproteinase hypothesis, there is a
constant or episodic release of proteinases, active at neutral pH, into
the lung parenchyma
• These proteinases come principally from inflammatory cells.
• Under normal conditions circulating proteinase inhibitors, especially α1 -
AT, and inhibitors produced locally in the lungs, permeate lung tissue and
prevent these proteinases from digesting the structural proteins of the
lungs.
• Emphysema results when the balance between proteinases and
antiproteinases in lung tissue tilts in favor of proteinases.
Proteinase inhibitor in the lung
• Proteolytic damage resulting in local loss of structural integrity of lung
tissue increases tissue susceptibility to proteinases.
• As some fibers are lost, the load on remaining fibers increases, propagating
mechanical failure analogous to mechanical failure of a partially cut rope
under strain.
• Biochemically, when lung tissue is overstretched new binding sites for
proteases are exposed, increasing the rate of proteolysis.
• Accordingly, a vicious cycle linking proteinases and tissue destruction may
exist.
LUNG ELASTIC FIBERS
• Because α1 -AT inhibits neutrophil elastase and papain is a potent elastase,
led to the concept that destruction of alveolar elastic fibers is key to
emphysema development.
• Proteinase–antiproteinase hypothesis of emphysema pathogenesis was
originally the “elastase–antielastase hypothesis.”
• Structurally, the extracellular matrix of the lung is organized into three
interdependent cable systems:
(1) an axial system that extends from the central airways through the
peripheral airways to the alveolar ducts;
(2) a parenchymal system that comprises the matrix of the alveolar septae;
and
(3) a peripheral system that arises from the visceral pleura and extends into
the interlobular septae, forming a fibrous sac around the lung
• Distal to the respiratory bronchioles, the axial system forms a helix
encircling the alveolar ducts, extending into the interstitium of alveolar
walls.
• Elastic fibers, reversible extensibility, come under tension and provide
elastic recoil throughout the respiratory cycle.
• Unlike elastic fibers, the interstitial collagen fibers in alveolar septa are
nondistensible and have high tensile strength.
• They can be thought of as relaxed ropes that straighten during inspiration
and become taut at total lung capacity
• Elastin is resistant to many proteinases, most notably the collagenases that
cleave interstitial collagens.
• However, there are a number of enzymes that may come into contact with
the lung that can degrade elastin.
• Elastic fibers in the lung normally last a full human life span.
• Histological studies of emphysematous lung tissue support the hypothesis
that elastic fibers are perturbed in emphysema.
• There are fragmented elastic fibers in α1 -AT deficiency and poorly
formed elastic fibers and clumps of elastin in smokers with
centriacinar emphysema.
• The latter changes appear to be from aberrant synthesis of new
elastin and resemble the findings in the lungs in emphysema induced
experimentally with elastase.
• The elastic fibers, like the elastic fibers in human emphysema, appear
disorganized.
• New elastin gene expression occurs even in severe emphysema in
humans
• There are significant barriers to effective repair of damaged elastic fibers in
the mature lung.
• When elastic fibers are damaged enough to fail under load, there is no
mechanism for cells to recreate a structure with a length many times the
size of each cell.
• The injured adult lung lacks the mechanical and morphogen gradients that
initiate alveolar formation during development, and may also be unable to
coordinate the expression of the many components necessary for functional
elastic fiber synthesis.
LUNG COLLAGEN TURNOVER

Expression of MMP-1 by alveolar epithelial cells in human emphysematous

tissue fits with the idea that collagenolytic activity plays a role in
emphysema.
• Analogous to elastin ,peptides promoting emphysema exposed to cigarette
smoke, a peptide derived from collagen, proline–glycine–proline (PGP), is a
neutrophil chemoattractant, associated with COPD
• PGP is generated by the sequential breakdown of collagen by MMPs 8 and
9.
• Blocking PGP reduces emphysema exposed to cigarette smoke.
• In emphysematous lungs the pores of Kohn are larger and more numerous
than in normal lungs.
• Because interstitial collagens and basement membrane collagens are
prominent in alveolar walls, it is plausible that collagenous structures
undergo degradation in the process of generating of these interalveolar
pores.
THANKYOU
ALPHA 1-ANTITRYPSIN DEFICIENCY
• Human plasma contains at least six proteins that function as proteinase
inhibitors.
• 10% of the total plasma protein.
• α1 -AT has the highest concentration of all of the plasma proteinase
inhibitors.
• α1-AT is a member of a family of serine proteinase inhibitors called serpins
(SERPINA1).
• α1 -AT is a glycoprotein of 52 kDa synthesized primarily by hepatocytes.
• Mononuclear phagocytes and bronchial epithelial cells are other less
abundant cellular sources.
• α1 -AT consists of a single polypeptide chain of 394 amino acids.
Carbohydrate side chains account for 12% of the α1 -AT molecular mass.
• The 12.2-kb gene, SERPINA1, that encodes α1 -AT is on the proteinase
inhibitor (PI) locus on chromosome 14.
• α1 -AT is an acute-phase reactant.
• Plasma levels rise with trauma, estrogen therapy, use of birth-control pills,
and during pregnancy.
• Inhibition of neutrophil elastase and other serine proteinases by α1 -AT
involves cleavage by the proteinase of the reactive site of α1 -AT between
methionine and serine and formation of an enzymeinhibitor complex that
renders the proteinase inactive.
• Because the complex is quite stable, inactivation is permanent.
• α1 -AT has a higher affinity for neutrophil elastase than trypsin or other
serine proteinases.
• . These include promoting immune tolerance, reducing production of
proinflammmatory cytokines, and protecting various cell types from
cell death through inhibition of caspases.
• α1 -AT disease is an autosomal recessive disorder,
 CLINICAL ASPECTS
• Severe α1 -AT deficiency may present in adults as chronic respiratory
symptoms (COPD, unremitting asthma, and bronchiectasis), liver disease,
(chronic virus–negative hepatitis, cirrhosis, and hepatoma) or skin disease
(panniculitis).
• 80% of patients are discovered because of respiratory symptoms and most
of the rest are detected by screening for α1 -AT deficiency.
• In middle-aged and older individuals with chronic respiratory symptoms,
the disease is often not diagnosed for more than 5 years after the onset of
the symptoms.
 Lung Disease
• The classic patient with Pi Z α1 -AT deficiency presents with the typical
symptoms of COPD, but is younger than usual, often around age 40.
• The patient has an increased total lung capacity, a decreased DLCO and
radiographic studies show hyperlucent lower lung fields reflecting the
predominance of emphysema in those regions .
• This classic patient reports a mild smoking history relative to the severity
of COPD and a family history of chronic respiratory symptoms in parents,
siblings, and other close relatives
• Wheezing, cough and sputum mimicking asthma, or chronic bronchitis, that
are poorly responsive to standard therapy may be the predominant
symptoms.
• Radiographic emphysema may be modest relative to the severity of the
airflow obstruction and may have upper lobe predominance of emphysema,.
• Discovery of SNPs in genes associated with COPD indicate that modifier
genes may account for the differences in COPD occurrence between
individuals who share the PiZ phenotype.
• It is advised that everyone diagnosed with COPD be screened for α1 -AT
deficiency.
Clinical Situations for Assessment of α1-AT
Status
• Individuals with moderate or more severe fixed airflow obstruction
undergoing routine pulmonary function testing , 0.63% had severe α1 -AT
deficiency (ZZ and SZ) and 10.88% were MS or MZ heterozygotes.
• Extrapolating these figures to the large number of people with COPD
countrywide yields a large number of severely deficient people.
• Smoking hastens the development of COPD in most people with severe α1 -
AT deficiency.
• The typical Pi Z individual who smokes has respiratory symptoms by age 40.
• Male gender and a history of asthma are also associated with worse lung
function among deficient individuals.
• Specific occupational exposures may also impart increased risk of disease,
but studies of non index cases and screened individuals confirm that
smoking is the predominant risk factor associated with increased mortality.
• Although emphysema is the predominant lung pathology associated with Pi
Z α1 -AT, bronchiectasis has been reported to be common.

• Among patients with bronchiectasis due to nontubercluous mycobacterial

(ATM) pulmonary infections, heterozygous α1 -AT abnormalities are
common.
THERAPY
• Therapy for COPD associated with α1 -AT deficiency includes the standard
measures for COPD— cessation of smoking, inhaled bronchodilators and
inhaled corticosteroids, pulmonary rehabilitation, pneumococcal and
influenza vaccinations, and supplemental oxygen .
• Lung volume reduction surgery has not proven as successful as in
individuals with normal α1 -AT.
• Up to the present time, the only specific treatment has been the so-called
augmentation therapy that consists of weekly intravenous administration of
α1 -AT isolated from pooled plasma obtained from healthy individuals, of
which several preparations are commercially available
• The effectiveness of augmentation therapy has been most evident in
individuals with reductions in FEV1 of 30% to 65% predicted.