ACUTE RESPONSES OF THE LUNG TO INJURY

MECHANISMS OF RESPIRATORY TRACT INJURYCertain gases and vapors stimulate nerve endings in the nose, particularly those of the trigeminal nerve.

Holding of breath or changes in breathing

patterns

Continued exposure…..

Cell necrosisIncreased permeability of the alveolar

walls

Acidic or alkaline irritants

Inhalation of high concentrations of HCl, NO2, NH3 or phosgene

At first, Produce very little apparent damage in the respiratory tract

After several hours…….

Epithelial barrier on the alveolar zone begins to leak, flooding the alveoli and producing a delayed

pulmonary edema

For highly reactive molecules such as OZONE….

Ozone lesions are propagated by a cascade of seondary reaction products and by reactive oxygen species arising from free radical reactions

Metabolism can also be involved in the pathogenesis of lung injury….

Cytochrome P450s 1A1, 2B1, 2F1, 4B1, and 3A4NADPH cytochrome P450 reductaseEpoxide hydrolaseFlavin-containing monooxygenases. Glutathione S-tranferasesGlutathione peroxidase

Cytosolic enzymes involved in xenobiotic

metabolism

OXIDATIVE BURDENCaused by free radicals, such as Ozone, NO2, tobacco smoke and lung defense cells

Oxidant species may mediate or promote the actions of pneumotoxicants.

When cellular injury of any type occurs, the release of otherwise contained cellular constituents may lead to extracellular generation of deleterious reactive O2 species.

Neutrophils, monocytes, and macrophages converts converts molecular O2 to reactive O2 metabolites.

Toxic O2 species are released into surrounding tissues.

Phagocytic production of active oxygen species causes inactivation of proteinase inhibitors and degranulation of mast cells.

AIRWAY REACTIVITYBronchial smooth muscles, help maintain airway tone and diameter during expansion and contraction of the lung.

Bronchial smooth muscle tone, is regulated by the ANS.

Bronchoconstriction can be proved by the ff:

Cigarette smokeAir pollutantsCholinergic drugs (acetylcholine)HistamineVarious prostaglandins and leukotrienesSubstance PNitric oxide

Bronchoconstriction causes…

DECREASE IN AIRWAY DIAMETERINCREASE IN RESISTANCE TO AIRFLOW

Symptoms:WheezingCoughingSensation of chest tightnessDyspnea

PULMONARY EDEMARepresents an acute, exudative phase of lung injury that alters ventilation-perfusion relationships and limits diffusive transfer of O2 and CO2 even in otherwise structurally normal alveoli.

CELL PROLIFERATIONEffects of toxicants on the lung may be reversible or irreversible.

The normal adult lung is an organ for which under normal circumstances very few cells appear to die and need to be replaced.

When damaged by a toxic insult, the lung parenchyma is capable or repairing itself.

Type I cell damage

Proliferation of type II epithelial cells

Transform into new type I cells

In the airways……Clara cells proliferate and divide following injury.

Migration of mobile blood cells such as leukocytes accross the pulmonary capillaries into the alveolar lumen may also trigger a mitotic response.

Capillary endothelial cells, interstitial cells, and alveolar macrophages also proliferate.

Excessive proliferation of fibroblasts may result in lung disease

In general, the lung appears to have a high capacity to repair itself and thus to deal with the many toxic insults presented by the environment.

CHRONIC RESPONSES OF THE LUNG TO INJURY

EMPHYSEMALungs become larger and too compliant, cause by destruction of the walls without fibrosis.

Major cause: cigarette smoke inhalation, although other toxicants elicit this response.

Toxicant induced= severe or recurrent inflammation

FIBROSISIncreased amounts of collagen

Resembles adult or infant respiratory distress syndrome

Excess lung collagen is usually observed not only in the alveolar interstitium, but also throughout the alveolar ducts and respiratory bronchioles.

ASTHMAShortness of breath, caused by narrowing of the large conducting airways.

Increased airway reactivity of the bronchial smooth muscle in response to exposure to irritants.

LUNG CANCERPotential mechanisms center on damage to DNA.

An activated carcinogen or its metabolic product may interact with DNA.

DNA damage caused by active oxygen species is another potentially important mechanism.

Ionizing radiation leads to the formation of superoxide.

Cigarette smoking contains high quantities of active oxygen species and other free radicals.

THE DEVELOPING LUNGUniquely sensitive to many airborne and blood-borne toxicants.

Development of lung occurs during both the prenatal and postnatal periods.

Stage of development during which toxicant exposure ooccurs may greatly influence the severity of lesion.