Chapter 15- The lung: ALI and ARDS

Question 1

What is ALI?

Answer 1

Acute lung injury (ALI) (also called noncardiogenic pulmonary edema) is characterized by the
abrupt onsetof significant hypoxemiaanddiffuse pulmonary infiltratesin theabsence of cardiac
failure

Question 2

What is ARDS?

Answer 2

Acute respiratory distress syndrome (ARDS) refers to severe ALI

Question 3

ARDS and ALI both
have:

Answer 3

inflammation-associated increase in pulmonary vascular permeability, and epithelial and
endothelial cell death.

Question 4

What is the histologic manifestion of both ALI and ARDS?

Answer 4

The histologic manifestation of these diseases is

diffuse alveolar damage
(DAD).

Question 5

Most cases of ALI are associated with an underlying etiology such as _____

Answer 5

sepsis.

Question 6

What is Acute Interstitial Pneumonia ( AIP)

Answer 6

In the
absence of any etiologic association of ALI , such cases are called acute interstitial pneumonia (AIP).

Question 7

ALI is a well-recognized complication of diverse conditions, including both direct injuries to the
lungs and systemic disorders ( Table 15-2 ). In many cases, a combination of predisposing
conditions is responsible (e.g., shock, oxygen therapy, and sepsis). Nonpulmonary organ
dysfunction may also be present in severe cases.

TABLE 15-2 – Conditions Associated with Development of Acute Respiratory Distress
Syndrome

Answer 7

• INFECTION
  
  • Sepsis [*]
  • Diffuse pulmonary infections [*]
  • Viral, Mycoplasma, and Pneumocystis pneumonia;
  • miliary tuberculosis
  • Gastric aspiration [*]
• PHYSICAL/INJURY
  
  • Mechanical trauma, including head
    injuries [*]
  • Pulmonary contusions
  • Near-drowning
  • Fractures with fat embolism
  • Burns
  • Ionizing radiation
• INHALED IRRITANTS
  
  • Oxygen toxicity
  • Smoke
  • Irritant gases
  • chemical
• CHEMICAL INJURY
  
  • Heroin or methadone overdose
  • Acetylsalicylic acid
  • Barbiturate overdose
  • Paraquat
• HEMATOLOGIC CONDITIONS
  
  • ​Multiple transfusions
  • Disseminated intravascular
    coagulation
• PANCREATITIS
• UREMIA
• CARDIOPULMONARY BYPASS
• HYPERSENSITIVITY REACTIONS
  
  • ​Organic solvents
  • Drugs

Question 8

More than 50% of cases of acute respiratory distress syndrome are associated with these four
conditions.

Answer 8

• Sepsis [*]
• Diffuse pulmonary infections [*]
  
  • Viral, Mycoplasma, and Pneumocystis pneumonia; miliary tuberculosis
• Gastric aspiration [*]
• Mechanical trauma, including head
  injuries [*]

Question 9

What is the morphology of the ALI in acutae stage?

Answer 9

In the acute stage, the lungs are heavy, firm, red, and boggy.

They exhibit congestion, interstitial and intra-alveolar edema, inflammation, fibrin deposition, and diffuse
alveolar damage.

The alveolar walls become lined with waxy hyaline membranes ( Fig. 15- 3 ) that are morphologically similar to those seen in hyaline membrane disease of neonates (
Chapter 10 ).

Alveolar hyaline membranes consist of fibrin-rich edema fluid mixed with the cytoplasmic and lipid remnants of necrotic epithelial cells.

Question 10

What is the morphology of ALI in organizing stage?

Answer 10

In the organizing stage, type II

• *pneumocytes undergo proliferation**, and there is a granulation tissue response in the alveolar
• *walls and in the alveolar spaces**.

In most cases the granulation tissue resolves, leaving
minimal functional impairment.

Sometimes, however, fibrotic thickening of the alveolar septa
ensues, caused by proliferation of interstitial cells and deposition of collagen.

Fatal cases
often have superimposed bronchopneumonia.

Question 11

Answer 11

FIGURE 15-3 Diffuse alveolar damage (acute respiratory distress syndrome). Some of the alveoli are collapsed; others are distended, and many are lined by hyaline membranes
(arrows).

Question 12

alveolar capillary membrane is formed by two separate barriers:

Answer 12

The alveolar capillary membrane is formed by two separate barriers:

• the microvascular endothelium and the
• alveolar epithelium.

Question 13

What is the pathophysiology of ARDS?

Answer 13

In ARDS the integrity of alveolar capillary membrane is formed by two separate barriers: the microvascular
endothelium and the alveolar epithelium, this barrier is compromised by either endothelial or epithelial injury or, more commonly, both

Question 14

Markers of endothelial
injury and activation such as____-can be detected at high
levels in the serum of patients with ARDS.

Answer 14

endothelin and von Willebrand factor

Question 15

What is the evidence of epithelial injury in the alveolar membrane?

Answer 15

Evidence of epithelial injury in the form of swelling,

• *vacuolization, bleb formation, and frank necrosis is also noted early in the course of acute lung
  injury. **

Question 16

What is the acute consequence of damage of alveolar capillary membrane?

Answer 16

The acute consequences of damage to the alveolar capillary membrane include:

• increased vascular permeability and alveolar flooding,
• loss of diffusion capacity, and
• widespread surfactant abnormalities caused by damage to type II pneumocytes.
• Endothelial injury also triggers the formation of microthrombi that add the insult of ischemic injury

Question 17

What is the characterisitc of ALI / ARDS?

Answer 17

Hyaline membranes so characteristic of ALI/ARDS result from inspissation of protein rich
edema fluid that entraps debris of dead alveolar epithelial cells.

Question 18

Answer 18

FIGURE 15-4 The normal alveolus (left side) compared with the injured alveolus in the early
phase of acute lung injury and acute respiratory distress syndrome.

Pro-inflammatory
cytokines such as interleukin 8 (IL-8), interleukin 1 (IL-1), and tumor necrosis factor (TNF)
(released by macrophages), cause neutrophils to adhere to pulmonary capillaries and extravasate into the alveolar space, where they undergo activation.

Activated neutrophils release a variety of factors, such as leukotrienes, oxidants, proteases, and platelet-activating factor (PAF), which contribute to local tissue damage, accumulation of edema fluid in the
airspaces, surfactant inactivation, and hyaline membrane formation.

Macrophage migration
inhibitory factor (MIF) released into the local milieu sustains the ongoing pro-inflammatory
response.

Subsequently, the release of macrophage-derived fibrogenic cytokines such as
transforming growth factor β (TGF-β)andplatelet-derived growth factor (PDGF) stimulate
fibroblast growth and collagen deposition associated with the healing phase of injury.

Question 19

Although the cellular and molecular basis of acute lung injury and ARDS remains an area of
active investigation,it appears that inARDS, lung injury is caused by an :

Answer 19

imbalance of proinflammatory
and anti-inflammatory mediators

Question 20

The most proximate signals leading to
uncontrolled activation of the acute inflammatory response are not yet understood.

However,
__________, a transcription factor whose activation itself is tightly regulated under
normal conditions, has emerged as a likely candidate shifting the balance in favor of a proinflammatory
state.

Answer 20

nuclear factor κB (NF-κB)

Question 21

What happens as early as 30 min after acute insult in the lungs?

Answer 21

• As early as 30 minutes after an acute insult, there is increased synthesis of

interleukin-8 (IL-8), a potent neutrophil chemotactic and activating agent, by pulmonary
macrophages.

• Release of this and similar compounds, such as IL-1 and tumor necrosis factor
• *(TNF),** leads to endothelial activation, and pulmonary microvascular sequestration and
• *activation of neutrophils.**

Question 22

______ are thought to have an important role in the pathogenesis
of ARDS.

Answer 22

Neutrophils

Histologic examination of lungs early in the disease process shows increased
numbers of neutrophilswithin the vascular space, the interstitium, and the alveoli.

Question 23

How
neutrophils are sequestered in the lung in ALI is not entirely clear.

There are two possible
mechanisms.

Answer 23

• Firstly, neutrophils that are activated by cytokines like IL-8 and TNF upregulate the expression of adhesion molecules that allow them to bind to their ligands on activated endothelial cells.
• Secondly, activated neutrophils become “stiff” and less deformable and thus get trapped in the narrow capillary beds of the lung.

Question 24

Activated neutrophils release a variety of
products (e.g., oxidants, proteases, platelet-activating factor, and leukotrienes) that cause damage to the alveolar epithelium and fuel the inflammatory cascade.

Combined assault on the
endothelium and epithelium perpetuate vascular leakiness and loss of surfactant that render
the alveolar unit unable to expand.

It should be noted that the destructive forces unleashed by neutrophils can be counteracted by an array of endogenous antiproteases, antioxidants, and
anti-inflammatory cytokines (e.g., IL-10) that are upregulated by pro-inflammatory cytokines.

Question 25

Dysregulation of the coagulation system is also a feature of ARDS.

T or F

Answer 25

T

“merong inflammation eh, may sugat eh”

Levels of tissue factor are
increased and those of the anticoagulant, protein C, are decreased in the plasma and
bronchoalveolar lavage fluid.

The coagulation pathway itself is a powerful pro-inflammatory signal.

Thrombin, for example, promotes adhesion of neutrophils to endothelium.

In the end, it is
the balance between the destructive and protective factors that determines the degree of tissue
injury and clinical severity of ALI/ARDS.

Question 26

Resolution of ARD requires:

Answer 26

Resolution of ARDS requires resorption of the exudate, removal of dead cells, and their
replacement by new endothelium and alveolar epithelial cells.

Removal of exudates and tissue
debris is accomplished by macrophages as in any other form of tissue injury.

Epithelial cells are
recovered by an initial proliferation of surviving type II pneumocytes that line the denuded
basement membrane.

The recently discovered bronchoalveolar stem cells may also participate.

Type II cells then give rise to type I cells that constitute the majority of alveolar epithelium.

Endothelial restoration occurs both by migration from uninjured capillaries and marrow-derived
endothelial progenitor cells( Chapter 3 ); the latter can be detected in the circulation during
recovery from ARDS.

Question 27

What can be detected in the circulation during recovery of ARDS?

Answer 27

marrow-derived
endothelial progenitor cells ( Chapter 3 ); the latter can be detected in the circulation during
recovery from ARDS.

Question 28

Desribe the Clinical Course of ALI.

Answer 28

Individuals who develop ALI are usually hospitalized for one of the predisposing conditions listed
earlier.

Profound dyspnea and tachypnea herald ALI, followed by increasing cyanosis and hypoxemia, respiratory failure, and the appearance of diffuse bilateral infiltrates on radiographic examination.

• *Hypoxemia can then become unresponsive to oxygen therapy,** due to
• *ventilation perfusion mismatching** as described below, and respiratory acidosis can develop.

Early in the course of the disease, lungs become stiff due to loss of functional surfactant.

In a
minority of patients, the exudate and diffuse tissue destruction that occur with ALI-ARDS do not
resolve and result in scarring.

The interstitial fibrosis in such cases produces stiff lungs and chronic pulmonary disease.

Question 29

The functional abnormalities in ALI are evenly distributed throughout the lungs.

T or F

Answer 29

True

The functional abnormalities in ALI are not evenly distributed throughout the lungs.

Question 30

The functional abnormalities in ALI are not evenly distributed throughout the lungs.

The lungs
can be divided into areas that are :

Answer 30

• infiltrated,
• consolidated,
• or collapsed (and thus poorly aerated and poorly compliant)
• and regions that have nearly normal levels of compliance and ventilation.

Poorly aerated regions continue to be perfused, producing ventilationperfusion mismatch and hypoxemia. Due to improvements in therapy for sepsis, mechanical ventilation, and supportive care, the mortality rate among the 190,000 ALI cases seen yearly in the United
States has decreased from 60% to about 40%. [5]

Question 31

The majority of deaths in ALI are attributable to
:

Answer 31

sepsis or multi-organ failure and, in some cases, direct lung injury.

Question 32

What is ACUTE INTERSTITIAL PNEUMONIA?

Answer 32

Acute interstitial pneumonia is a clinicopathologic term that is used to describe widespread ALI

• *associated with a rapidly progressive clinical course that is of unknownetiology (sometimes**
• *referred to as idiopathic ALI-DAD)**.

It is an uncommon disease occurring at a mean age of 50 years with no sex predilection.

Patients present with acute respiratory failure often following an illness of less than 3 weeks’ duration that resembles an upper respiratory tract infection.

The
radiographic and pathologic features are identical to those of the organizing stage of ALI.

The
mortality rate varies from 33% to 74%, with most deaths occurring within 1 to 2 months. [7]

In
the surviving patients, recurrences and chronic interstitial disease may develop.